Macrocyclic compounds for treating disease

ABSTRACT

The present disclosure relates to certain macrocyclic derivatives, pharmaceutical compositions containing them, and methods of using them to treat disease, such as cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/866,983, filed on May 5, 2020, which is a continuation of U.S. patentapplication Ser. No. 16/777,717, filed on Jan. 30, 2020, which is acontinuation which claims priority under 35 U.S.C. § 120 toInternational Application No. PCT/US2018/066158 filed on Dec. 18, 2018,which claims priority under 35 U.S.C. § 119(e) to U.S. ProvisionalApplication Ser. No. 62/607,528 filed on Dec. 19, 2017, U.S. ProvisionalApplication Ser. No. 62/727,124 filed on Sep. 5, 2018, and U.S.Provisional Application Ser. No. 62/779,283 filed on Dec. 13, 2018, theentire disclosures of which are incorporated herein by reference.

TECHNICAL FIELD

The present disclosure relates to certain macrocyclic derivatives,pharmaceutical compositions containing them, and methods of using themto treat disease, such as cancer.

BACKGROUND

Protein kinases regulate various functions in the cell including cellgrowth, proliferation and survival. Dysregulation of protein kinases isoften the cause of many solid malignancies (Manning G. et al. Science.2002, 298, 1912-1934). The use of protein kinase inhibitors has led tosubstantial clinical benefit in patients harboring oncogenicaberrations. More than thirty protein kinase inhibitors have beenapproved for clinical treatment of cancer (Berndt N. et al. Curr. Opin.Chem. Biol. 2017, 39:126-132). RET is a receptor tyrosine kinase thatwas initially discovered in 1985 through transfection of NIH3T3 cellswith human lymphoma DNA (Takahashi, M. et al. Cell. 1985, 42:581-588.).RET is expressed with its highest levels in early embryogenesis (duringwhich it has diverse roles in different tissues) and decreases torelatively low levels in normal adult tissues Pachnis, V., et al.Development 1993, 119, 1005-1017). RET plays a critical role in thedevelopment of enteric nervous system and kidneys during embryogenesis(Schuchardt, A. et al. Nature 1994, 367:380-383). RET activationregulates the downstream signalling pathways (RAS/MAPK/ERK, PI3K/AKT,and JAK-STAT etc.), leading to cellular proliferation, migration, anddifferentiation (Mulligan, L M. Nat Rev Cancer. 2014, 14(3):173-86).

Gain-of-function mutations of RET with constitutive activation have beenfound in heritable and sporadic tumors including activating pointmutations within the full-length RET protein or genomic rearrangementsthat produce chimeric RET oncoproteins in the cytosol. The heritableoncogenic RET mutations are found in multiple endocrine neoplasia type 2(MEN2) including medullary thyroid cancer (MTC) and familial MTC withmore than 80 pathogenic variants spanning RET exons 5-16 reported(Mulligan, L M. Nat Rev Cancer. 2014, 14(3):173-86). Among them, RETM918T and RET A883F are found in 40-65% of sporadic MTC. The somaticmutation, chimeric RET fusion oncoproteins have been identified insporadic tumors. The RET rearrangements are originally reported inpapillary thyroid cancers (PTCs) (Grieco, M. et al. Cell. 1990, 23; 60(4):557-63.). The resulting fusion transcripts composed of the 3′ end ofRET kinase domain and the 5′ end of separate partner genes (CCDC6,NCOA4, TRIM24, TRIM33, PRKAR1A, GOLGA5, KTN1, ERC1, MBD1, and TRIM27etc.). RET fusions are identified in approximately 20%-40% of PTCs, andCCDC6-RET and NCOA4-RET are the most commonly identified RET fusions inPTCs (Drilon A, et al. Nat Rev Clin Oncol. 2017 Nov. 14. doi:10.1038/nrclinonc.2017.175). RET gene fusions are also found inapproximately 1%-2% of non-small cell lung cancer (NSCLC) (Gainor J F,Shaw A T. Oncologist. 2013, 18(7):865-75), and over 50% of RET fusionsin NSCLC is KIF5B-RET, representing the most frequent RET fusion form.However, the RET inhibitors have relatively low response rates and shorttreatment duration in the treatment of NSCLC patients with KIF5B-RETfusion gene in multiple clinical trials (Drilon, A. Nat Rev Clin Oncol.2017 Nov. 14. doi:10.1038/nrclinonc. 2017.175). It was reported that thekinesin and kinase domains of KIF5B-RET act together to establish anemergent microtubule and RAB-vesicle-dependent RET-SRC-EGFR-FGFRsignaling hub (Das T K and Cagan R L Cell Rep. 2017, 20(10):2368-2383).The inhibition of SRC kinase will have the potential to stop therecruitment of multiple RTKs via the N terminus of the KIF5B-RET fusionprotein and the oncogenic signaling to increase the therapeuticefficiency of RET inhibitors. In addition, Src family tyrosine kinasesregulate MTC cellular proliferation in vitro and mediate growth signalsby increasing DNA synthesis and decreasing apoptosis (Liu Z, et al. J.Clin. Endocrinol. Metab. 2004, 89, 3503-3509). Therefore, a dualinhibitor of RET and SRC represents a highly desired therapeuticintervention to maximally target abnormal RET signaling in cancers.

SUMMARY

In one aspect, the disclosure relates to a compound of the formula I

wherein

L is independently —C(R¹)(R²)— or X;

X is —O—, —S—, —S(O)— or —S(O)₂—;

each R¹ and R² is independently H, deuterium, halogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, —OR^(a),—OC(O)R^(a), —OC(O)R^(a), —OC(O)NR^(a)R^(b), —OS(O)R^(a), —OS(O)₂R^(a),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b),—OS(O)NR^(a)R^(b), —OS(O)₂NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)OR^(b), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)S(O)R^(b),—NR^(a)S(O)₂R^(b), —NR^(a)S(O)NR^(a)R^(b), —NR^(a)S(O)₂NR^(a)R^(b),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b), —PR^(a)R^(b),—P(O)R^(a)R^(b), —P(O)₂R^(a)R^(b), —P(O)NR^(a)R^(b), —P(O)₂NR^(a)R^(b),—P(O)OR^(a), —P(O)₂OR^(a), —CN, or —NO₂, or R¹ and R² taken togetherwith the carbon or carbons to which they are attached form a C₃-C₆cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogenatom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3-to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, mono- or bicyclicheteroaryl, 4- to 6-membered heterocycloalkyl is independentlyoptionally substituted by deuterium, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, —OR^(e), —OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f),—OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f), —NR^(e)S(O)₂R^(f),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e),—P(O)₂OR^(e), —CN, or —NO₂;

M is CR³ or N;

M¹ is CR⁴;

each R³, R⁴, and R⁵ is independently hydrogen, deuterium, halogen,—OR^(c), —OC(O)R^(c), —OC(O)NR^(e)R^(d), —OC(═N)NR^(e)R^(d),—OS(O)R^(c), —OS(O)₂R^(c), —OS(O)NR^(e)R^(d), —OS(O)₂NR^(e)R^(d),—SR^(c), —S(O)R^(c), —S(O)₂R^(c), —S(O)NR^(e)R^(d), —S(O)₂NR^(e)R^(d),—NR^(e)R^(d), —NR^(c)C(O)R^(d), —NR^(c′)C(O)OR^(d),—NR^(c)C(O)NR^(c)R^(d), —NR^(c)C(═N)NR^(c)R^(d), —NR^(c)S(O)R^(d),—NR^(c)S(O)₂R^(d), —NR^(c)S(O)NR^(c)R^(d), —NR^(c)S(O)₂NR^(c)R^(d),—C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(d), —C(═N)NR^(c)R^(d),—PR^(c)R^(d), —P(O)R^(c)R^(d), —P(O)₂R^(c)R^(d), —P(O)NR^(c)R^(d),—P(O)₂NR^(c)R^(d), —P(O)OR^(c), —P(O)₂OR^(c), —CN, —NO₂, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, or R⁴and R⁵ taken together with the ring to which they are attached form aC₅-C₈cycloalkyl, or a 5- to 8-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, mono- orbicyclic heteroaryl, C₅-C₈cycloalkyl, or 5- to 8-memberedheterocycloalkyl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OR^(e), —OC(O)R^(e),—OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f), —NR^(e)R^(f), —NR^(e)C(O)R^(f),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f),—NR^(e)S(O)₂R^(f), —NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f),—C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f),—P(O)R^(e)R^(f), —P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f),—P(O)OR^(e), —P(O)₂OR^(e), —CN, or —NO₂;

R⁶ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- orbicyclic heteroaryl, wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl isindependently optionally substituted by deuterium, halogen, —OR^(e),—OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e),—S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f), —NR^(e)S(O)₂R^(f),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e),—P(O)₂OR^(e), —CN, or —NO₂;

R⁷ and R⁸ combine to form a C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl isindependently optionally substituted by deuterium, halogen, —OR^(e),—OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e),—S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f), —NR^(e)S(O)₂R^(f),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e),—P(O)₂OR^(e), —CN, or —NO₂;

Y is O, S, NR⁹, or CR⁹R¹⁰;

R⁹ and R¹⁰ are each independently H, deuterium, halogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- orbicyclic heteroaryl is optionally substituted by a halogen, —OR^(e),—OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e),—S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f), —NR^(e)S(O)₂R^(f),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e), or—P(O)₂OR^(e);

each R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f) is independentlyselected from the group consisting of H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, 5- to 7-membered heteroaryl;

each of Z¹, Z², Z³, Z⁴, Z⁵, and Z⁶ is independently N, NH, C or CH;

p is 1, 2, 3, or 4; and

t is 1, 2, 3, 4, or 5;

or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure relates to a compound of the formula I

wherein

L is independently —C(R¹)(R²)— or X;

X is O, S, S(O) or S(O)₂;

each R¹ and R² is independently H, deuterium, halogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, —OR^(a),—OC(O)R^(a), —OC(O)R^(a), —OC(O)NR^(a)R^(b), —OS(O)R^(a), —OS(O)₂R^(a),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b),—OS(O)NR^(a)R^(b), —OS(O)₂NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)OR^(b), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)S(O)R^(b),—NR^(a)S(O)₂R^(b), —NR^(a)S(O)NR^(a)R^(b), —NR^(a)S(O)₂NR^(a)R^(b),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b), —PR^(a)R^(b),—P(O)R^(a)R^(b), —P(O)₂R^(a)R^(b), —P(O)NR^(a)R^(b), —P(O)₂NR^(a)R^(b),—P(O)OR^(a), —P(O)₂OR^(a), —CN, or —NO₂, or R¹ and R² taken togetherwith the carbon or carbons to which they are attached form a C₃-C₆cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogenatom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3-to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, mono- or bicyclicheteroaryl, 4- to 6-membered heterocycloalkyl is independentlyoptionally substituted by deuterium, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, —OR^(e),—OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e),—S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(t), —NR^(e)C(O)OR^(t),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f), —NR^(e)S(O)₂R^(f),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e),—P(O)₂OR^(e), —CN, or —NO₂;

M is CR³ or N;

M¹ is CR⁴;

each R³, R⁴, and R⁵ is independently hydrogen, deuterium, halogen,—OR^(c), —OC(O)R^(c), —OC(O)NR^(e)R^(d), —OC(═N)NR^(e)R^(d),—OS(O)R^(c), —OS(O)₂R^(c), —OS(O)NR^(e)R^(d), —OS(O)₂NR^(e)R^(d),—SR^(c), —S(O)R^(c), —S(O)₂R^(c), —S(O)NR^(e)R^(d), —S(O)₂NR^(e)R^(d),—NR^(e)R^(d), —NR^(c)C(O)R^(d), —NR^(c′)C(O)OR^(d),—NR^(c)C(O)NR^(c)R^(d), —NR^(c)C(═N)NR^(c)R^(d), —NR^(c)S(O)R^(d),—NR^(c)S(O)₂R^(d), —NR^(c)S(O)NR^(c)R^(d), —NR^(c)S(O)₂NR^(c)R^(d),—C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(d), —C(═N)NR^(c)R^(d),—PR^(c)R^(d), —P(O)R^(c)R^(d), —P(O)₂R^(e)R^(d), —P(O)NR^(e)R^(d),—P(O)₂NR^(e)R^(d), —P(O)OR^(c), —P(O)₂OR^(c), —CN, —NO₂, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, or R⁴and R⁵ taken together with the ring to which they are attached form aC₅-C₈cycloalkyl, or a 5- to 8-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, mono- orbicyclic heteroaryl, C₅-C₈cycloalkyl, or 5- to 8-memberedheterocycloalkyl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OR^(e), —OC(O)R^(e),—OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f), —NR^(e)R^(f), —NR^(e)C(O)R^(f),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f),—NR^(e)S(O)₂R^(f), —NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f),—C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f),—P(O)R^(e)R^(f), —P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f),—P(O)OR^(e), —P(O)₂OR^(e), —CN, or —NO₂;

R⁶ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- orbicyclic heteroaryl, wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl isindependently optionally substituted by deuterium, halogen, C₃-C₆cycloalkyl, or 5- to 7-membered heterocycloalkyl, —OR^(e), —OC(O)R^(e),—OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f), —NR^(e)R^(f), —NR^(e)C(O)R^(f),—NR^(e)C(O)OR^(t), —NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f),—NR^(e)S(O)₂R^(f), —NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f),—C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f),—P(O)R^(e)R^(f), —P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f),—P(O)OR^(e), —P(O)₂OR^(e), —CN, or —NO₂;

R⁷ and R⁸ combine to form a C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl isindependently optionally substituted by deuterium, halogen, —OR^(e),—OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e),—S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f), —NR^(e)S(O)₂R^(f),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e),—P(O)₂OR^(e), —CN, or —NO₂;

Y is O, S, NR⁹, or CR⁹R¹⁰;

R⁹ and R¹⁰ are each independently H, deuterium, halogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- orbicyclic heteroaryl is optionally substituted by a halogen, —OR^(e),—OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e),—S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f), —NR^(e)S(O)₂R^(f),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e), or—P(O)₂OR^(e);

each R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f) is independentlyselected from the group consisting of H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, 5- to 7-membered heteroaryl;

each of Z¹, Z², Z³, Z⁴, Z⁵, and Z⁶ is independently N, NH, C or CH;

p is 1, 2, 3, or 4; and

t is 1, 2, 3, 4, or 5;

or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure relates to a compound or apharmaceutically acceptable salt thereof, having the formula II

wherein

M is CR³ or N;

M¹ is CR⁴;

X is O, S, S(O), or S(O)₂;

each R¹ and R² is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —OR^(a), —SR^(a),—NR^(a)R^(b), —C(O)OR^(a), —C(O)NR^(a)R^(b); wherein each hydrogen atomin C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl andC₆-C₁₀ aryl is independently optionally substituted by deuterium,halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆alkyl)₂, —OC(O)NH(C₁-C₆ alkyl), —OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂,—OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆alkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆ alkyl)C(O)OH,—NHS(O)C₁-C₆ alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl,—N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —C(O)C₁-C₆ alkyl, —CO₂H, —C(O)OC₁-C₆ alkyl,—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl,—S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl),—S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)NH₂, —S(O)₂NH₂, —OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂N(C₁-C₆ alkyl)₂,—OS(O)NH(C₁-C₆ alkyl), —OS(O)₂NH(C₁-C₆ alkyl), —OS(O)NH₂, —OS(O)₂NH₂,—P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to7-membered heterocycloalkyl;

R³, R⁴, and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

R⁷ and R⁸ combine to form a C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl isindependently optionally substituted by deuterium, halogen, —OH, —OC₁-C₆alkyl, —OC(O)C₁-C₆ alkyl, —OC(O)NH₂, —OC(O)NH(C₁-C₆ alkyl),—OC(O)N(C₁-C₆ alkyl)₂, —OC(═N)NH₂, —OC(═N)NH(C₁-C₆ alkyl),—OC(═N)N(C₁-C₆ alkyl)₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆ alkyl,—OS(O)NH₂, —OS(O)NH(C₁-C₆ alkyl), —OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂NH₂,—OS(O)₂NH(C₁-C₆ alkyl), —OS(O)₂N(C₁-C₆ alkyl)₂, —SH, —SC₁-C₆ alkyl,—S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH₂, —S(O)NH(C₁-C₆ alkyl),—S(O)(C₁-C₆ alkyl)₂, —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂N(C₁-C₆alkyl)₂, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)OH, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OH, —N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH₂,—N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂,—NHS(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —NHS(O)₂C₁-C₆ alkyl,—N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂NH₂, —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —C(O)C₁-C₆ alkyl, —C(O)OC₁-C₆ alkyl,—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, —P(O)₂(C₁-C₆ alkyl)₂, —P(O)NH₂, —P(O)NH(C₁-C₆alkyl), —P(O)N(C₁-C₆ alkyl)₂, —P(O)₂NH₂, —P(O)₂NH(C₁-C₆ alkyl),—P(O)₂N(C₁-C₆ alkyl)₂, —P(O)OH, —P(O)OC₁-C₆ alkyl, —P(O)₂OH,—P(O)₂OC₁-C₆ alkyl, —CN, or —NO₂;

Y is O, S, NR⁹, or CR⁹R¹⁰;

R⁹ and R¹⁰ are each independently H, deuterium, halogen, or C₁-C₆ alkyl,wherein each hydrogen atom in C₁-C₆ alkyl is optionally substituted by ahalogen, —OH, —OC₁-C₆ alkyl, —OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆ alkyl)₂,—OC(O)NH(C₁-C₆ alkyl), —OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂,—OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆alkyl, —OS(O)N(C₁-C₆ alkyl)₂, —OS(O)NH(C₁-C₆ alkyl), —OS(O)NH₂,—OS(O)₂N(C₁-C₆ alkyl)₂, —OS(O)₂NH(C₁-C₆ alkyl), —OS(O)₂NH₂, —SH, —SC₁-C₆alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)N(C₁-C₆ alkyl)₂,—S(O)NH(C₁-C₆ alkyl), —S(O)NH₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —NH₂, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)OC₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)OH, —NHC(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆alkyl)C(O)N(C₁C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁C₆ alkyl), —N(C₁-C₆alkyl)C(O)NH₂, —NHC(O)N(C₁C₆ alkyl)₂, —NHC(O)NH(C₁C₆ alkyl), —NHC(O)NH₂,—N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —NHS(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)NH₂,—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)NH₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —NHS(O)₂NH(C₁-C₆alkyl), —NHS(O)₂NH₂, —C(O)C₁-C₆ alkyl, —C(O)OC₁-C₆ alkyl, —C(O)N(C₁-C₆alkyl)₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆alkyl)₂, —P(O)₂(C₁-C₆ alkyl)₂, —P(O)N(C₁-C₆ alkyl)₂, —P(O)₂N(C₁-C₆alkyl)₂, —P(O)OC₁-C₆ alkyl, or —P(O)₂OC₁-C₆ alkyl;

each of Z¹, Z², Z³, Z⁴, Z⁵, and Z⁶ is independently N, NH, C or CH; and

n is 2 or 3.

In another aspect, the disclosure relates to a compound selected fromthe group consisting of

wherein

M is CR³ or N;

M¹ is CR⁴;

X is O, S, S(O), or S(O)₂;

R¹ and R² are each independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —OR^(a), —SR^(a),—NR^(a)R^(b), —C(O)OR^(a), —C(O)NR^(a)R^(b); wherein each hydrogen atomin C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl andC₆-C₁₀ aryl is independently optionally substituted by deuterium,halogen, —OH, —CN, —OC₁-C₆ alkyl, —OC₁-C₆ alkyl(C₆-C₁₀ aryl), —NH₂,—OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆ alkyl)₂, —OC(O)NH(C₁-C₆ alkyl),—OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂, —OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂,—OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆ alkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆ alkyl)C(O)OH, —NHS(O)C₁-C₆alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂,—N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂,—C(O)C₁-C₆ alkyl, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl,—S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)NH₂, —S(O)₂NH₂,—OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂N(C₁-C₆ alkyl)₂, —OS(O)NH(C₁-C₆ alkyl),—OS(O)₂NH(C₁-C₆ alkyl), —OS(O)NH₂, —OS(O)₂NH₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

R³, R⁴, and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

R⁷ and R⁸ combine to form a C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl isindependently optionally substituted by deuterium, halogen, —OH, —OC₁-C₆alkyl, —OC(O)C₁-C₆ alkyl, —OC(O)NH₂, —OC(O)NH(C₁-C₆ alkyl),—OC(O)N(C₁-C₆ alkyl)₂, —OC(═N)NH₂, —OC(═N)NH(C₁-C₆ alkyl),—OC(═N)N(C₁-C₆ alkyl)₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆ alkyl,—OS(O)NH₂, —OS(O)NH(C₁-C₆ alkyl), —OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂NH₂,—OS(O)₂NH(C₁-C₆ alkyl), —OS(O)₂N(C₁-C₆ alkyl)₂, —SH, —SC₁-C₆ alkyl,—S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH₂, —S(O)NH(C₁-C₆ alkyl),—S(O)(C₁-C₆ alkyl)₂, —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂N(C₁-C₆alkyl)₂, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)OH, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OH, —N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH₂,—N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂,—NHS(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —NHS(O)₂C₁-C₆ alkyl,—N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂NH₂, —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —C(O)C₁-C₆ alkyl, —C(O)OC₁-C₆ alkyl,—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, —P(O)₂(C₁-C₆ alkyl)₂, —P(O)NH₂, —P(O)NH(C₁-C₆alkyl), —P(O)N(C₁-C₆ alkyl)₂, —P(O)₂NH₂, —P(O)₂NH(C₁-C₆ alkyl),—P(O)₂N(C₁-C₆ alkyl)₂, —P(O)OH, —P(O)OC₁-C₆ alkyl, —P(O)₂OH,—P(O)₂OC₁-C₆ alkyl, —CN, or —NO₂;

Y is O, S, NR⁹, or CR⁹R¹⁰; and

R⁹ and R¹⁰ are each independently H, deuterium, halogen, or C₁-C₆ alkyl,wherein each hydrogen atom in C₁-C₆ alkyl is optionally substituted by ahalogen, —OH, —OC₁-C₆ alkyl, —OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆ alkyl)₂,—OC(O)NH(C₁-C₆ alkyl), —OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂,—OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆alkyl, —OS(O)N(C₁-C₆ alkyl)₂, —OS(O)NH(C₁-C₆ alkyl), —OS(O)NH₂,—OS(O)₂N(C₁-C₆ alkyl)₂, —OS(O)₂NH(C₁-C₆ alkyl), —OS(O)₂NH₂, —SH, —SC₁-C₆alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)N(C₁-C₆ alkyl)₂,—S(O)NH(C₁-C₆ alkyl), —S(O)NH₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —NH₂, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)OC₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)OH, —NHC(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆alkyl)C(O)N(C₁C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁C₆ alkyl), —N(C₁-C₆alkyl)C(O)NH₂, —NHC(O)N(C₁C₆ alkyl)₂, —NHC(O)NH(C₁C₆ alkyl), —NHC(O)NH₂,—N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —NHS(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)NH₂,—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)NH₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —NHS(O)₂NH(C₁-C₆alkyl), —NHS(O)₂NH₂, —C(O)C₁-C₆ alkyl, —C(O)OC₁-C₆ alkyl, —C(O)N(C₁-C₆alkyl)₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆alkyl)₂, —P(O)₂(C₁-C₆ alkyl)₂, —P(O)N(C₁-C₆ alkyl)₂, —P(O)₂N(C₁-C₆alkyl)₂, —P(O)OC₁-C₆ alkyl, or —P(O)₂OC₁-C₆ alkyl.

Additional embodiments, features, and advantages of the disclosure willbe apparent from the following detailed description and through practiceof the disclosure. The compounds of the present disclosure can bedescribed as embodiments in any of the following enumerated clauses. Itwill be understood that any of the embodiments described herein can beused in connection with any other embodiments described herein to theextent that the embodiments do not contradict one another.

1. A compound of the formula I

wherein

L is independently —C(R¹)(R²)— or X;

X is —O—, —S—, —S(O)— or —S(O)₂—;

each R¹ and R² is independently H, deuterium, halogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, —OR^(a),—OC(O)R^(a), —OC(O)R^(a), —OC(O)NR^(a)R^(b), —OS(O)R^(a), —OS(O)₂R^(a),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b),—OS(O)NR^(a)R^(b), —OS(O)₂NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)OR^(b), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)S(O)R^(b),—NR^(a)S(O)₂R^(b), —NR^(a)S(O)NR^(a)R^(b), —NR^(a)S(O)₂NR^(a)R^(b),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b), —PR^(a)R^(b),—P(O)R^(a)R^(b), —P(O)₂R^(a)R^(b), —P(O)NR^(a)R^(b), —P(O)₂NR^(a)R^(b),—P(O)OR^(a), —P(O)₂OR^(a), —CN, or —NO₂, or R¹ and R² taken togetherwith the carbon or carbons to which they are attached form a C₃-C₆cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogenatom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3-to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, mono- or bicyclicheteroaryl, 4- to 6-membered heterocycloalkyl is independentlyoptionally substituted by deuterium, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, —OR^(e), —OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f),—OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(t), —NR^(e)C(O)OR^(t),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f), —NR^(e)S(O)₂R^(f),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e),—P(O)₂OR^(e), —CN, or —NO₂;

M is CR³ or N;

M¹ is CR⁴;

each R³, R⁴, and R⁵ is independently hydrogen, deuterium, halogen,—OR^(c), —OC(O)R^(c), —OC(O)NR^(c)R^(d), —OC(═N)NR^(c)R^(d),—OS(O)R^(c), —OS(O)₂R^(c), —OS(O)NR^(c)R^(d), —OS(O)₂NR^(c)R^(d),—SR^(c), —S(O)R^(c), —S(O)₂R^(c), —S(O)NR^(c)R^(d), —S(O)₂NR^(c)R^(d),—NR^(c)R^(d), —NR^(c)C(O)R^(d), —NR^(c′)C(O)OR^(d),—NR^(c)C(O)NR^(e)R^(d), —NR^(e)C(═N)NR^(e)R^(d), —NR^(c)S(O)R^(d),—NR^(c)S(O)₂R^(d), —NR^(c)S(O)NR^(e)R^(d), —NR^(c)S(O)₂NR^(e)R^(d),—C(O)R^(c), —C(O)OR^(c), —C(O)NR^(e)R^(d), —C(═N)NR^(e)R^(d),—PR^(e)R^(d), —P(O)R^(e)R^(d), —P(O)₂R^(c)R^(d), —P(O)NR^(c)R^(d),—P(O)₂NR^(c)R^(d), —P(O)OR^(c), —P(O)₂OR^(c), —CN, —NO₂, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, or R⁴and R⁵ taken together with the ring to which they are attached form aC₅-C₈ cycloalkyl, or a 5- to 8-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, mono- orbicyclic heteroaryl, C₅-C₈ cycloalkyl, or 5- to 8-memberedheterocycloalkyl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OR^(e), —OC(O)R^(e),—OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f), —NR^(e)R^(f), —NR^(e)C(O)R^(f),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f),—NR^(e)S(O)₂R^(f), —NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f),—C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f),—P(O)R^(e)R^(f), —P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f),—P(O)OR^(e), —P(O)₂OR^(e), —CN, or —NO₂;

R⁶ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- orbicyclic heteroaryl, wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl isindependently optionally substituted by deuterium, halogen, —OR^(e),—OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e),—S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(t), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(t), —NR^(e)S(O)₂R^(t),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e),—P(O)₂OR^(e), —CN, or —NO₂;

R⁷ and R⁸ combine to form a C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl isindependently optionally substituted by deuterium, halogen, —OR^(e),—OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e),—S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(t), —NR^(e)C(O)OR^(t),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(t), —NR^(e)S(O)₂R^(f),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e),—P(O)₂OR^(e), —CN, or —NO₂;

Y is O, S, NR⁹, or CR⁹R¹⁰;

R⁹ and R¹⁰ are each independently H, deuterium, halogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- orbicyclic heteroaryl is optionally substituted by a halogen, —OR^(e),—OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e),—S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(t), —NR^(e)C(O)OR^(t),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(t), —NR^(e)S(O)₂R^(f),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e), or—P(O)₂OR^(e);

each R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f) is independentlyselected from the group consisting of H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, 5- to 7-membered heteroaryl;

each of Z¹, Z², Z³, Z⁴, Z⁵, and Z⁶ is independently N, NH, C or CH;

p is 1, 2, 3, or 4; and

t is 1, 2, 3, 4, or 5;

or a pharmaceutically acceptable salt thereof.

1a. A compound of the formula I

wherein

L is independently —C(R¹)(R²)— or X;

X is O, S, S(O) or S(O)₂;

each R¹ and R² is independently H, deuterium, halogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, —OR^(a),—OC(O)R^(a), —OC(O)R^(a), —OC(O)NR^(a)R^(b), —OS(O)R^(a), —OS(O)₂R^(a),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b),—OS(O)NR^(a)R^(b), —OS(O)₂NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)OR^(b), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)S(O)R^(b),—NR^(a)S(O)₂R^(b), —NR^(a)S(O)NR^(a)R^(b), —NR^(a)S(O)₂NR^(a)R^(b),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b), —PR^(a)R^(b),—P(O)R^(a)R^(b), —P(O)₂R^(a)R^(b), —P(O)NR^(a)R^(b), —P(O)₂NR^(a)R^(b),—P(O)OR^(a), —P(O)₂OR^(a), —CN, or —NO₂, or R¹ and R² taken togetherwith the carbon or carbons to which they are attached form a C₃-C₆cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogenatom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3-to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, mono- or bicyclicheteroaryl, 4- to 6-membered heterocycloalkyl is independentlyoptionally substituted by deuterium, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, —OR^(e),—OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e),—S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(t), —NR^(e)C(O)OR^(t),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(t), —NR^(e)S(O)₂R^(t),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e),—P(O)₂OR^(e), —CN, or —NO₂;

M is CR³ or N;

M¹ is CR⁴;

each R³, R⁴, and R⁵ is independently hydrogen, deuterium, halogen,—OR^(c), —OC(O)R^(c), —OC(O)NR^(c)R^(d), —OC(═N)NR^(c)R^(d),—OS(O)R^(c), —OS(O)₂R^(c), —OS(O)NR^(c)R^(d), —OS(O)₂NR^(c)R^(d),—SR^(c), —S(O)R^(c), —S(O)₂R^(c), —S(O)NR^(c)R^(d), —S(O)₂NR^(c)R^(d),—NR^(c)R^(d), —NR^(c)C(O)R^(d), —NR^(c′)C(O)OR^(d),—NR^(c)C(O)NR^(c)R^(d), —NR^(c)C(═N)NR^(c)R^(d), —NR^(c)S(O)R^(d),—NR^(c)S(O)₂R^(d), —NR^(c)S(O)NR^(c)R^(d), —NR^(c)S(O)₂NR^(c)R^(d),—C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(d), —C(═N)NR^(c)R^(d),—PR^(c)R^(d), —P(O)R^(c)R^(d), —P(O)₂R^(e)R^(d), —P(O)NR^(e)R^(d),—P(O)₂NR^(e)R^(d), —P(O)OR^(c), —P(O)₂OR^(c), —CN, —NO₂, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, or R⁴and R⁵ taken together with the ring to which they are attached form aC₅-C₈ cycloalkyl, or a 5- to 8-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, mono- orbicyclic heteroaryl, C₅-C₈ cycloalkyl, or 5- to 8-memberedheterocycloalkyl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OR^(e), —OC(O)R^(e),—OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f), —NR^(e)R^(f), —NR^(e)C(O)R^(f),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f),—NR^(e)S(O)₂R^(f), —NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f),—C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f),—P(O)R^(e)R^(f), —P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f),—P(O)OR^(e), —P(O)₂OR^(e), —CN, or —NO₂;

R⁶ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- orbicyclic heteroaryl, wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl isindependently optionally substituted by deuterium, halogen, C₃-C₆cycloalkyl, or 5- to 7-membered heterocycloalkyl, —OR^(e), —OC(O)R^(e),—OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f), —NR^(e)R^(f), —NR^(e)C(O)R^(f),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f),—NR^(e)S(O)₂R^(f), —NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f),—C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f),—P(O)R^(e)R^(f), —P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f),—P(O)OR^(e), —P(O)₂OR^(e), —CN, or —NO₂;

R⁷ and R⁸ combine to form a C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl isindependently optionally substituted by deuterium, halogen, —OR^(e),—OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e),—S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f), —NR^(e)S(O)₂R^(f),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e),—P(O)₂OR^(e), —CN, or —NO₂;

Y is O, S, NR⁹, or CR⁹R¹⁰;

R⁹ and R¹⁰ are each independently H, deuterium, halogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- orbicyclic heteroaryl is optionally substituted by a halogen, —OR^(e),—OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e),—S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f), —NR^(e)S(O)₂R^(f),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e), or—P(O)₂OR^(e);

each R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f) is independentlyselected from the group consisting of H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, 5- to 7-membered heteroaryl;

each of Z¹, Z², Z³, Z⁴, Z⁵, and Z⁶ is independently N, NH, C or CH;

p is 1, 2, 3, or 4; and

t is 1, 2, 3, 4, or 5;

or a pharmaceutically acceptable salt thereof.

2. The compound of clause 1, or a pharmaceutically acceptable saltthereof, wherein p is 1.

3. The compound of clause 1 or 2, or a pharmaceutically acceptable saltthereof, wherein t is 3.

3a. The compound of clause 1 or 2, or a pharmaceutically acceptable saltthereof, wherein t is 3 or 4.

4. The compound of clause 1, or a pharmaceutically acceptable saltthereof, having the formula II

wherein

M is CR³ or N;

M¹ is CR⁴;

X is O, S, S(O), or S(O)₂;

each R¹ and R² is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —OR^(a), —SR^(a),—NR^(a)R^(b), —C(O)OR^(a), —C(O)NR^(a)R^(b); wherein each hydrogen atomin C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl andC₆-C₁₀ aryl is independently optionally substituted by deuterium,halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆alkyl)₂, —OC(O)NH(C₁-C₆ alkyl), —OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂,—OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆alkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆ alkyl)C(O)OH,—NHS(O)C₁-C₆ alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl,—N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —C(O)C₁-C₆ alkyl, —CO₂H, —C(O)OC₁-C₆ alkyl,—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl,—S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl),—S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)NH₂, —S(O)₂NH₂, —OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂N(C₁-C₆ alkyl)₂,—OS(O)NH(C₁-C₆ alkyl), —OS(O)₂NH(C₁-C₆ alkyl), —OS(O)NH₂, —OS(O)₂NH₂,—P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to7-membered heterocycloalkyl;

R³, R⁴, and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

R⁷ and R⁸ combine to form a C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl isindependently optionally substituted by deuterium, halogen, —OH, —OC₁-C₆alkyl, —OC(O)C₁-C₆ alkyl, —OC(O)NH₂, —OC(O)NH(C₁-C₆ alkyl),—OC(O)N(C₁-C₆ alkyl)₂, —OC(═N)NH₂, —OC(═N)NH(C₁-C₆ alkyl),—OC(═N)N(C₁-C₆ alkyl)₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆ alkyl,—OS(O)NH₂, —OS(O)NH(C₁-C₆ alkyl), —OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂NH₂,—OS(O)₂NH(C₁-C₆ alkyl), —OS(O)₂N(C₁-C₆ alkyl)₂, —SH, —SC₁-C₆ alkyl,—S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH₂, —S(O)NH(C₁-C₆ alkyl),—S(O)(C₁-C₆ alkyl)₂, —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂N(C₁-C₆alkyl)₂, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)OH, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OH, —N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH₂,—N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂,—NHS(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —NHS(O)₂C₁-C₆ alkyl,—N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂NH₂, —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —C(O)C₁-C₆ alkyl, —C(O)OC₁-C₆ alkyl,—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, —P(O)₂(C₁-C₆ alkyl)₂, —P(O)NH₂, —P(O)NH(C₁-C₆alkyl), —P(O)N(C₁-C₆ alkyl)₂, —P(O)₂NH₂, —P(O)₂NH(C₁-C₆ alkyl),—P(O)₂N(C₁-C₆ alkyl)₂, —P(O)OH, —P(O)OC₁-C₆ alkyl, —P(O)₂OH,—P(O)₂OC₁-C₆ alkyl, —CN, or —NO₂;

Y is O, S, NR⁹, or CR⁹R¹⁰;

R⁹ and R¹⁰ are each independently H, deuterium, halogen, or C₁-C₆ alkyl,wherein each hydrogen atom in C₁-C₆ alkyl is optionally substituted by ahalogen, —OH, —OC₁-C₆ alkyl, —OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆ alkyl)₂,—OC(O)NH(C₁-C₆ alkyl), —OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂,—OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆alkyl, —OS(O)N(C₁-C₆ alkyl)₂, —OS(O)NH(C₁-C₆ alkyl), —OS(O)NH₂,—OS(O)₂N(C₁-C₆ alkyl)₂, —OS(O)₂NH(C₁-C₆ alkyl), —OS(O)₂NH₂, —SH, —SC₁-C₆alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)N(C₁-C₆ alkyl)₂,—S(O)NH(C₁-C₆ alkyl), —S(O)NH₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —NH₂, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)OC₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)OH, —NHC(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆alkyl)C(O)N(C₁C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁C₆ alkyl), —N(C₁-C₆alkyl)C(O)NH₂, —NHC(O)N(C₁C₆ alkyl)₂, —NHC(O)NH(C₁C₆ alkyl), —NHC(O)NH₂,—N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —NHS(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)NH₂,—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)NH₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —NHS(O)₂NH(C₁-C₆alkyl), —NHS(O)₂NH₂, —C(O)C₁-C₆ alkyl, —C(O)OC₁-C₆ alkyl, —C(O)N(C₁-C₆alkyl)₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆alkyl)₂, —P(O)₂(C₁-C₆ alkyl)₂, —P(O)N(C₁-C₆ alkyl)₂, —P(O)₂N(C₁-C₆alkyl)₂, —P(O)OC₁-C₆ alkyl, or —P(O)₂OC₁-C₆ alkyl;

each of Z¹, Z², Z³, Z⁴, Z⁵, and Z⁶ is independently N, NH, C or CH; and

n is 2 or 3.

5. The compound of any of the preceding clause, having the formula III

or a pharmaceutically acceptable salt thereof.

6. The compound of clause 4 or 5, or a pharmaceutically acceptable saltthereof, wherein n is 2.

6a. The compound of clause 4 or 5, or a pharmaceutically acceptable saltthereof, wherein n is 2 or 3.

7. The compound of any one of the preceding clauses, having the formulaIV

or a pharmaceutically acceptable salt thereof.

7a. The compound of any one of the preceding clauses, having the formulaIV or V

or a pharmaceutically acceptable salt thereof.

8. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein Y is O.

9. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein M is CR³.

10. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein R³ is H, deuterium,C₁-C₆ alkyl or halogen.

11. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein R³ is H or F.

12. The compound of any one of clauses 1 to 8, or a pharmaceuticallyacceptable salt thereof, wherein M is N.

13. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein M¹ is CR⁴.

14. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein R⁴ is H, deuterium,C₁-C₆ alkyl or halogen.

15. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein R⁴ is H or Cl.

16. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein R⁵ is F.

17. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein R² is H.

17a. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein at least one of R² isH.

18. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein R¹ is H.

18a. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein at least one of R¹ isH.

19. The compound of any one of clauses 1 to 17, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is C₁-C₆ alkyl.

19a. The compound of any one of clauses 1 to 17, or a pharmaceuticallyacceptable salt thereof, wherein at least one of R¹ is C₁-C₆ alkyl.

20. The compound of any one of clauses 1 to 17, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is H, and R² is C₁-C₆ alkyl.

20a. The compound of any one of clauses 1 to 16, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is H, and R² is C₁-C₆ alkyl; or R¹is C₁-C₆ alkyl, and R² is H; or R¹ is H or C₁-C₆ alkyl, and R² is H; orR¹ is H, and R² is C₃-C₇ cycloalkyl; or R¹ is C₃-C₇ cycloalkyl, and R²is H; or wherein one of R¹ is C₁-C₆ alkyl, any other R¹, when present,is H, and any R², when present, is H.

21. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein R⁷ and R⁸ combine toform a 5- or 6-membered cycloalkyl, wherein each hydrogen atom in the 5-or 6-membered cycloalkyl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —OC₁-C₆ alkyl(C₆-C₁₀ aryl),—NH₂, —OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆ alkyl)₂, —OC(O)NH(C₁-C₆ alkyl),—OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂, —OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂,—OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆ alkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆ alkyl)C(O)OH, —NHS(O)C₁-C₆alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂,—N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂,—C(O)C₁-C₆ alkyl, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl,—S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)NH₂, —S(O)₂NH₂,—OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂N(C₁-C₆ alkyl)₂, —OS(O)NH(C₁-C₆ alkyl),—OS(O)₂NH(C₁-C₆ alkyl), —OS(O)NH₂, —OS(O)₂NH₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl.

21a. The compound of any one of the preceding clauses, or apharmaceutically acceptable salt thereof, wherein R⁷ and R⁸ combine toform a 4-, 5- or 6-membered cycloalkyl, wherein each hydrogen atom inthe 5- or 6-membered cycloalkyl is independently optionally substitutedby deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —OC₁-C₆ alkyl(C₆-C₁₀aryl), —NH₂, —OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆ alkyl)₂, —OC(O)NH(C₁-C₆alkyl), —OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂, —OC(═N)NH(C₁-C₆ alkyl),—OC(═N)NH₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆ alkyl, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆ alkyl)C(O)OH, —NHS(O)C₁-C₆alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂,—N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂,—C(O)C₁-C₆ alkyl, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl,—S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)NH₂, —S(O)₂NH₂,—OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂N(C₁-C₆ alkyl)₂, —OS(O)NH(C₁-C₆ alkyl),—OS(O)₂NH(C₁-C₆ alkyl), —OS(O)NH₂, —OS(O)₂NH₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl.

22. The compound of any one of clauses 1 to 20, or a pharmaceuticallyacceptable salt thereof, wherein R⁷ and R⁸ combine to form a 3-, 4-, 5-or 6-membered heterocycloalkyl, wherein each hydrogen atom in the 3-,4-, 5- or 6-membered heterocycloalkyl is independently optionallysubstituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —OC₁-C₆alkyl(C₆-C₁₀ aryl), —NH₂, —OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆ alkyl)₂,—OC(O)NH(C₁-C₆ alkyl), —OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂,—OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆alkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆ alkyl)C(O)OH,—NHS(O)C₁-C₆ alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl,—N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —C(O)C₁-C₆ alkyl, —CO₂H, —C(O)OC₁-C₆ alkyl,—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl,—S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl),—S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)NH₂, —S(O)₂NH₂, —OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂N(C₁-C₆ alkyl)₂,—OS(O)NH(C₁-C₆ alkyl), —OS(O)₂NH(C₁-C₆ alkyl), —OS(O)NH₂, —OS(O)₂NH₂,—P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to7-membered heterocycloalkyl.

23. The compound of clause 22, or a pharmaceutically acceptable saltthereof, wherein R⁷ and R⁸ combine to form a tetrahydrofuran ring.

24. The compound of clause 21, or a pharmaceutically acceptable saltthereof, wherein R⁷ and R⁸ combine to form a cyclopentane ring.

24a. The compound of clause 21 or 21a, or a pharmaceutically acceptablesalt thereof, wherein R⁷ and R⁸ combine to form a cyclobutane ring,cyclopentane ring, or cyclohexane ring.

25. The compound of clause 1, or a pharmaceutically acceptable saltthereof, selected form the group consisting of

wherein

M is CR³ or N;

M¹ is CR⁴;

X is O, S, S(O), or S(O)₂;

R¹ and R² are each independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —OR^(a), —SR^(a),—NR^(a)R^(b), —C(O)OR^(a), —C(O)NR^(a)R^(b); wherein each hydrogen atomin C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl andC₆-C₁₀ aryl is independently optionally substituted by deuterium,halogen, —OH, —CN, —OC₁-C₆ alkyl, —OC₁-C₆ alkyl(C₆-C₁₀ aryl), —NH₂,—OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆ alkyl)₂, —OC(O)NH(C₁-C₆ alkyl),—OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂, —OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂,—OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆ alkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆ alkyl)C(O)OH, —NHS(O)C₁-C₆alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂,—N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂,—C(O)C₁-C₆ alkyl, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl,—S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)NH₂, —S(O)₂NH₂,—OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂N(C₁-C₆ alkyl)₂, —OS(O)NH(C₁-C₆ alkyl),—OS(O)₂NH(C₁-C₆ alkyl), —OS(O)NH₂, —OS(O)₂NH₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

R³, R⁴, and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆alkyl, —OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or—CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

R⁷ and R⁸ combine to form a C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₃-C₇ cycloalkyl, a 5- to 8-memberedheterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroaryl isindependently optionally substituted by deuterium, halogen, —OH, —OC₁-C₆alkyl, —OC(O)C₁-C₆ alkyl, —OC(O)NH₂, —OC(O)NH(C₁-C₆ alkyl),—OC(O)N(C₁-C₆ alkyl)₂, —OC(═N)NH₂, —OC(═N)NH(C₁-C₆ alkyl),—OC(═N)N(C₁-C₆ alkyl)₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆ alkyl,—OS(O)NH₂, —OS(O)NH(C₁-C₆ alkyl), —OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂NH₂,—OS(O)₂NH(C₁-C₆ alkyl), —OS(O)₂N(C₁-C₆ alkyl)₂, —SH, —SC₁-C₆ alkyl,—S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH₂, —S(O)NH(C₁-C₆ alkyl),—S(O)(C₁-C₆ alkyl)₂, —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂N(C₁-C₆alkyl)₂, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)OH, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OH, —N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH₂,—N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂,—NHS(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —NHS(O)₂C₁-C₆ alkyl,—N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂NH₂, —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —C(O)C₁-C₆ alkyl, —C(O)OC₁-C₆ alkyl,—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, —P(O)₂(C₁-C₆ alkyl)₂, —P(O)NH₂, —P(O)NH(C₁-C₆alkyl), —P(O)N(C₁-C₆ alkyl)₂, —P(O)₂NH₂, —P(O)₂NH(C₁-C₆ alkyl),—P(O)₂N(C₁-C₆ alkyl)₂, —P(O)OH, —P(O)OC₁-C₆ alkyl, —P(O)₂OH,—P(O)₂OC₁-C₆ alkyl, —CN, or —NO₂;

Y is O, S, NR⁹, or CR⁹R¹⁰; and

R⁹ and R¹⁰ are each independently H, deuterium, halogen, or C₁-C₆ alkyl,wherein each hydrogen atom in C₁-C₆ alkyl is optionally substituted by ahalogen, —OH, —OC₁-C₆ alkyl, —OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆ alkyl)₂,—OC(O)NH(C₁-C₆ alkyl), —OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂,—OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆alkyl, —OS(O)N(C₁-C₆ alkyl)₂, —OS(O)NH(C₁-C₆ alkyl), —OS(O)NH₂,—OS(O)₂N(C₁-C₆ alkyl)₂, —OS(O)₂NH(C₁-C₆ alkyl), —OS(O)₂NH₂, —SH, —SC₁-C₆alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)N(C₁-C₆ alkyl)₂,—S(O)NH(C₁-C₆ alkyl), —S(O)NH₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —NH₂, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)OC₁-C₆alkyl, —N(C₁-C₆ alkyl)C(O)OH, —NHC(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆alkyl)C(O)N(C₁C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁C₆ alkyl), —N(C₁-C₆alkyl)C(O)NH₂, —NHC(O)N(C₁C₆ alkyl)₂, —NHC(O)NH(C₁C₆ alkyl), —NHC(O)NH₂,—N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —NHS(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)NH₂,—NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)NH₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —NHS(O)₂NH(C₁-C₆alkyl), —NHS(O)₂NH₂, —C(O)C₁-C₆ alkyl, —C(O)OC₁-C₆ alkyl, —C(O)N(C₁-C₆alkyl)₂, —C(O)NH(C₁-C₆ alkyl), —C(O)NH₂, —P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆alkyl)₂, —P(O)₂(C₁-C₆ alkyl)₂, —P(O)N(C₁-C₆ alkyl)₂, —P(O)₂N(C₁-C₆alkyl)₂, —P(O)OC₁-C₆ alkyl, or —P(O)₂OC₁-C₆ alkyl.

26. The compound of clause 25, or a pharmaceutically acceptable saltthereof, wherein M is CR³.

27. The compound of clause 25 or 26, or a pharmaceutically acceptablesalt thereof, wherein R³ is H, deuterium, C₁-C₆ alkyl or halogen.

28. The compound of any one of clauses 25 to 27, or a pharmaceuticallyacceptable salt thereof, wherein R³ is H or F.

29. The compound of clause 25, or a pharmaceutically acceptable saltthereof, wherein M is N.

30. The compound of any one of clauses 25 to 29, or a pharmaceuticallyacceptable salt thereof, wherein M¹ is CR⁴.

31. The compound of any one of clauses 25 to 30, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is H, deuterium, C₁-C₆ alkyl orhalogen.

32. The compound of any one of clauses 25 to 31, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is H or Cl.

33. The compound of any one of clauses 25 to 32, or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is F.

34. The compound of any one of clauses 25 to 33, or a pharmaceuticallyacceptable salt thereof, wherein R² is H.

35. The compound of any one of clauses 25 to 34, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is C₁-C₆ alkyl.

36. The compound of any one of clauses 25 to 33, or a pharmaceuticallyacceptable salt thereof, wherein R² is C₁-C₆ alkyl.

36a. The compound of any one of clauses 25 to 33, or a pharmaceuticallyacceptable salt thereof, wherein R² is C₁-C₆ alkyl; or C₃-C₇ cycloalkyl.

37. The compound of any one of clauses 25 to 36, or a pharmaceuticallyacceptable salt thereof, wherein R⁷ and R⁸ combine to form a 5- or6-membered cycloalkyl, wherein each hydrogen atom in the 5- or6-membered cycloalkyl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —OC₁-C₆ alkyl(C₆-C₁₀ aryl),—NH₂, —OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆ alkyl)₂, —OC(O)NH(C₁-C₆ alkyl),—OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂, —OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂,—OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆ alkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆ alkyl)C(O)OH, —NHS(O)C₁-C₆alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂,—N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂,—C(O)C₁-C₆ alkyl, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl,—S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)NH₂, —S(O)₂NH₂,—OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂N(C₁-C₆ alkyl)₂, —OS(O)NH(C₁-C₆ alkyl),—OS(O)₂NH(C₁-C₆ alkyl), —OS(O)NH₂, —OS(O)₂NH₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl.

37a. The compound of any one of clauses 25 to 36, or a pharmaceuticallyacceptable salt thereof, wherein R⁷ and R⁸ combine to form a 4-, 5- or6-membered cycloalkyl, wherein each hydrogen atom in the 5- or6-membered cycloalkyl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —OC₁-C₆ alkyl(C₆-C₁₀ aryl),—NH₂, —OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆ alkyl)₂, —OC(O)NH(C₁-C₆ alkyl),—OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂, —OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂,—OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆ alkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆ alkyl)C(O)OH, —NHS(O)C₁-C₆alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂,—N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂,—C(O)C₁-C₆ alkyl, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl,—S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)NH₂, —S(O)₂NH₂,—OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂N(C₁-C₆ alkyl)₂, —OS(O)NH(C₁-C₆ alkyl),—OS(O)₂NH(C₁-C₆ alkyl), —OS(O)NH₂, —OS(O)₂NH₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl.

38. The compound of any one of clauses 25 to 36, or a pharmaceuticallyacceptable salt thereof, wherein R⁷ and R⁸ combine to form a 3-, 4-, 5-or 6-membered heterocycloalkyl, wherein each hydrogen atom in the 3-,4-, 5- or 6-membered heterocycloalkyl is independently optionallysubstituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —OC₁-C₆alkyl(C₆-C₁₀ aryl), —NH₂, —OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆ alkyl)₂,—OC(O)NH(C₁-C₆ alkyl), —OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂,—OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆alkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆ alkyl)C(O)OH,—NHS(O)C₁-C₆ alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl,—N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —C(O)C₁-C₆ alkyl, —CO₂H, —C(O)OC₁-C₆ alkyl,—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl,—S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl),—S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)NH₂, —S(O)₂NH₂, —OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂N(C₁-C₆ alkyl)₂,—OS(O)NH(C₁-C₆ alkyl), —OS(O)₂NH(C₁-C₆ alkyl), —OS(O)NH₂, —OS(O)₂NH₂,—P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to7-membered heterocycloalkyl.

39. The compound of clause 38, or a pharmaceutically acceptable saltthereof, wherein R⁷ and R⁸ combine to form a tetrahydrofuran ring.

40. The compound of clause 37, or a pharmaceutically acceptable saltthereof, wherein R⁷ and R⁸ combine to form a cyclopentane ring.

40a. The compound of clause 37 or 37a, or a pharmaceutically acceptablesalt thereof, wherein R⁷ and R⁸ combine to form a cyclobutane ring,cyclopentane ring, or cyclohexane ring.

41. The compound of any of the preceding clauses, or a pharmaceuticallyacceptable salt thereof, wherein X is O.

42. The compound of clause 1, selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

43. A pharmaceutical composition comprising a compound of any one of thepreceding clauses, or a pharmaceutically acceptable salt thereof, andoptionally at least one diluent, carrier or excipient.

44. A method of treating cancer comprising administering to a subject inneed of such treatment an effective amount of at least one compound ofany one of clauses 1 to 42, or a pharmaceutically acceptable saltthereof.

45. Use of a compound of any one of clauses 1 to 42, or apharmaceutically acceptable salt thereof, in the preparation of amedicament for the treatment of cancer.

46. Use of a compound of any one of clauses 1 to 42, or apharmaceutically acceptable salt thereof, for treating cancer.

47. A method of inhibiting RET or SRC, comprising contacting a cellcomprising one or more of such kinases with an effective amount of atleast one compound of any one of clauses 1 to 42, or a pharmaceuticallyacceptable salt thereof, and/or with at least one pharmaceuticalcomposition of the disclosure, wherein the contacting is in vitro, exvivo, or in vivo.

48. A compound of any one of clauses 1 to 42, for use in treating cancerin a patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the pharmacodynamic inhibiting activity of Compound 5 onRET in RET-driven cells, specifically that Compound 5 caused thesuppression of RET autophosphorylation at IC50s of around 0.3 nM in TT.

FIG. 2 shows the pharmacodynamic inhibiting activity of Compound 5 onRET in RET-driven cells, specifically that Compound 5 caused thesuppression of RET autophosphorylation at IC50s of around 1-3 nM inBa/F3 KIF5B-RET WT.

FIG. 3 shows the pharmacodynamic inhibiting activity of Compound 5 onRET in RET-driven cells, specifically that Compound 5 caused thesuppression of RET autophosphorylation at IC50s of around 3-10 nM inBa/F3 KIF5B-RET G810R.

FIG. 4A is a chart that shows that Compound 5 dosed at 2 mg/kg BID and 5mg/kg BID for 27 days decreased tumor size in test mice compared tountreated control. Untreated control (

), 2 mg/kg (

), 5 mg/kg (

).

FIG. 4B is a chart that shows % weight change for test mice dosed at 2mg/kg BID and 5 mg/kg BID for 27 days compared to untreated control.Untreated control (

), 2 mg/kg (

), 5 mg/kg (

).

FIG. 5A is a chart that shows the effect of Compound 5 dosed at 1 mg/kgBID and 5 mg/kg BID for 10 days on tumor size in test mice compared tountreated control. Untreated control (

), 1 mg/kg (

), 5 mg/kg (

).

FIG. 5B is a chart that shows % weight change for test mice dosed at 1mg/kg BID and 5 mg/kg BID for 10 days compared to untreated control.Untreated control (

), 1 mg/kg (

), 5 mg/kg (

).

FIG. 6A is a chart that shows the effect of Compound 5 dosed at 1 mg/kgBID, 5 mg/kg BID, and 10 mg/kg BID for 14 days on tumor size in testmice compared to untreated control. Untreated control (

), 1 mg/kg (

), 5 mg/kg (

), 10 mg/kg (

).

FIG. 6B is a chart that shows % weight change for test mice dosed at 1mg/kg BID, 5 mg/kg BID, and 10 mg/kg BID for 14 days compared tountreated control. Untreated control (

), 1 mg/kg (

), 5 mg/kg (

), 10 mg/kg (

).

FIG. 7A is a chart that shows the effect of Compound 5 dosed at 1 mg/kgBID and 5 mg/kg BID for 21 days on tumor size in test mice compared tountreated control. Untreated control (

), 1 mg/kg (

), 5 mg/kg (

).

FIG. 7B is a chart that shows % weight change for test mice dosed at 1mg/kg BID and 5 mg/kg BID for 21 days compared to untreated control.Untreated control (

), 1 mg/kg (

), 5 mg/kg (

).

FIG. 8A is a chart that shows the effect of Compound 5 dosed at 1 mg/kg,2 mg/kg, or 5 mg/kg BID for 10 days on tumor size in test mice comparedto untreated control. Untreated control (

), 1 mg/kg (

), 2 mg/kg (

), 5 mg/kg (

). FIG. 8B is a chart that shows the effect of Compound 5 dosed at 1mg/kg, 2 mg/kg, or 5 mg/kg BID for 10 days on body weight in test micecompared to untreated control. Untreated control (

), 1 mg/kg (

), 2 mg/kg (

), 5 mg/kg (

).

DETAILED DESCRIPTION

Before the present disclosure is further described, it is to beunderstood that this disclosure is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present disclosure will be limited only by the appendedclaims.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this disclosure belongs. All patents, applications,published applications and other publications referred to herein areincorporated by reference in their entireties. If a definition set forthin this section is contrary to or otherwise inconsistent with adefinition set forth in a patent, application, or other publication thatis herein incorporated by reference, the definition set forth in thissection prevails over the definition incorporated herein by reference.

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural referents unless the context clearly dictatesotherwise. It is further noted that the claims may be drafted to excludeany optional element. As such, this statement is intended to serve asantecedent basis for use of such exclusive terminology as “solely,”“only” and the like in connection with the recitation of claim elements,or use of a “negative” limitation.

As used herein, the terms “including,” “containing,” and “comprising”are used in their open, non-limiting sense.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

Except as otherwise noted, the methods and techniques of the presentembodiments are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, NewYork: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith andMarch, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, Fifth Edition, Wiley-Interscience, 2001.

Chemical nomenclature for compounds described herein has generally beenderived using the commercially-available ACD/Name 2014 (ACD/Labs) orChemBioDraw Ultra 13.0 (Perkin Elmer).

It is appreciated that certain features of the disclosure, which are,for clarity, described in the context of separate embodiments, may alsobe provided in combination in a single embodiment. Conversely, variousfeatures of the disclosure, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables arespecifically embraced by the present disclosure and are disclosed hereinjust as if each and every combination was individually and explicitlydisclosed, to the extent that such combinations embrace compounds thatare stable compounds (i.e., compounds that can be isolated,characterized, and tested for biological activity). In addition, allsubcombinations of the chemical groups listed in the embodimentsdescribing such variables are also specifically embraced by the presentdisclosure and are disclosed herein just as if each and every suchsub-combination of chemical groups was individually and explicitlydisclosed herein.

Definitions

As used herein, the term “alkyl” includes a chain of carbon atoms, whichis optionally branched and contains from 1 to 20 carbon atoms. It is tobe further understood that in certain embodiments, alkyl may beadvantageously of limited length, including C₁-C₁₂, C₁-C₁₀, C₁-C₉,C₁-C₈, C₁-C₇, C₁-C₆, and C₁-C₄, Illustratively, such particularlylimited length alkyl groups, including C₁-C₈, C₁-C₇, C₁-C₆, and C₁-C₄,and the like may be referred to as “lower alkyl.” Illustrative alkylgroups include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl,3-pentyl, neopentyl, hexyl, heptyl, octyl, and the like. Alkyl may besubstituted or unsubstituted. Typical substituent groups includecycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,mercapto, alkylthio, arylthio, cyano, halo, carbonyl, oxo, (═O),thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, C-carboxy, O-carboxy, nitro, and amino, or asdescribed in the various embodiments provided herein. It will beunderstood that “alkyl” may be combined with other groups, such as thoseprovided above, to form a functionalized alkyl. By way of example, thecombination of an “alkyl” group, as described herein, with a “carboxy”group may be referred to as a “carboxyalkyl” group. Other non-limitingexamples include hydroxyalkyl, aminoalkyl, and the like.

As used herein, the term “alkenyl” includes a chain of carbon atoms,which is optionally branched, and contains from 2 to 20 carbon atoms,and also includes at least one carbon-carbon double bond (i.e. C═C). Itwill be understood that in certain embodiments, alkenyl may beadvantageously of limited length, including C₂-C₁₂, C₂-C₉, C₂-C₈, C₂-C₇,C₂-C₆, and C₂-C₄. Illustratively, such particularly limited lengthalkenyl groups, including C₂-C₈, C₂-C₇, C₂-C₆, and C₂-C₄ may be referredto as lower alkenyl. Alkenyl may be unsubstituted, or substituted asdescribed for alkyl or as described in the various embodiments providedherein. Illustrative alkenyl groups include, but are not limited to,ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.

As used herein, the term “alkynyl” includes a chain of carbon atoms,which is optionally branched, and contains from 2 to 20 carbon atoms,and also includes at least one carbon-carbon triple bond (i.e. C≡C). Itwill be understood that in certain embodiments, alkynyl may each beadvantageously of limited length, including C₂-C₁₂, C₂-C₉, C₂-C₈, C₂-C₇,C₂-C₆, and C₂-C₄. Illustratively, such particularly limited lengthalkynyl groups, including C₂-C₈, C₂-C₇, C₂-C₆, and C₂-C₄ may be referredto as lower alkynyl. Alkenyl may be unsubstituted, or substituted asdescribed for alkyl or as described in the various embodiments providedherein. Illustrative alkenyl groups include, but are not limited to,ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.

As used herein, the term “aryl” refers to an all-carbon monocyclic orfused-ring polycyclic groups of 6 to 12 carbon atoms having a completelyconjugated pi-electron system. It will be understood that in certainembodiments, aryl may be advantageously of limited size such as C₆-C₁₀aryl. Illustrative aryl groups include, but are not limited to, phenyl,naphthylenyl and anthracenyl. The aryl group may be unsubstituted, orsubstituted as described for alkyl or as described in the variousembodiments provided herein.

As used herein, the term “cycloalkyl” refers to a 3 to 15 memberall-carbon monocyclic ring, including an all-carbon 5-member/6-member or6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a“fused” ring system means that each ring in the system shares anadjacent pair of carbon atoms with each other ring in the system) group,or a carbocyclic ring that is fused to another group such as aheterocyclic, such as ring 5- or 6-membered cycloalkyl fused to a 5- to7-membered heterocyclic ring, where one or more of the rings may containone or more double bonds but the cycloalkyl does not contain acompletely conjugated pi-electron system. It will be understood that incertain embodiments, cycloalkyl may be advantageously of limited sizesuch as C₃-C₁₃, C₃-C₉, C₃-C₆ and C₄-C₆. Cycloalkyl may be unsubstituted,or substituted as described for alkyl or as described in the variousembodiments provided herein. Illustrative cycloalkyl groups include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl,norbornyl, norbornenyl, 9H-fluoren-9-yl, and the like. Illustrativeexamples of cycloalkyl groups shown in graphical representations includethe following entities, in the form of properly bonded moieties:

As used herein, the term “heterocycloalkyl” refers to a monocyclic orfused ring group having in the ring(s) from 3 to 12 ring atoms, in whichat least one ring atom is a heteroatom, such as nitrogen, oxygen orsulfur, the remaining ring atoms being carbon atoms. Heterocycloalkylmay optionally contain 1, 2, 3 or 4 heteroatoms. A heterocycloalkylgroup may be fused to another group such as another heterocycloalkyl, ora heteroaryl group. Heterocycloalkyl may also have one or more doublebonds, including double bonds to nitrogen (e.g. C═N or N═N) but does notcontain a completely conjugated pi-electron system. It will beunderstood that in certain embodiments, heterocycloalkyl may beadvantageously of limited size such as 3- to 7-memberedheterocycloalkyl, 5- to 7-membered heterocycloalkyl, 3-, 4-, 5- or6-membered heterocycloalkyl, and the like. Heterocycloalkyl may beunsubstituted, or substituted as described for alkyl or as described inthe various embodiments provided herein. Illustrative heterocycloalkylgroups include, but are not limited to, oxiranyl, thianaryl, azetidinyl,oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl,oxepanyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2, 3, 4-tetrahydropyridinyl, and the like. Illustrative examples ofheterocycloalkyl groups shown in graphical representations include thefollowing entities, in the form of properly bonded moieties:

As used herein, the term “heteroaryl” refers to a monocyclic or fusedring group of 5 to 12 ring atoms containing one, two, three or four ringheteroatoms selected from nitrogen, oxygen and sulfur, the remainingring atoms being carbon atoms, and also having a completely conjugatedpi-electron system. It will be understood that in certain embodiments,heteroaryl may be advantageously of limited size such as 3- to7-membered heteroaryl, 5- to 7-membered heteroaryl, and the like.Heteroaryl may be unsubstituted, or substituted as described for alkylor as described in the various embodiments provided herein. Illustrativeheteroaryl groups include, but are not limited to, pyrrolyl, furanyl,thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl,pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl,pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl,isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl,benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl andcarbazoloyl, and the like. Illustrative examples of heteroaryl groupsshown in graphical representations, include the following entities, inthe form of properly bonded moieties:

As used herein, “hydroxy” or ““hydroxyl” refers to an —OH group.

As used herein, “alkoxy” refers to both an —O-(alkyl) or an—O-(unsubstituted cycloalkyl) group. Representative examples include,but are not limited to, methoxy, ethoxy, propoxy, butoxy,cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

As used herein, “aryloxy” refers to an —O-aryl or an —O-heteroarylgroup. Representative examples include, but are not limited to, phenoxy,pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, andthe like, and the like.

As used herein, “mercapto” refers to an —SH group.

As used herein, “alkylthio” refers to an —S-(alkyl) or an—S-(unsubstituted cycloalkyl) group. Representative examples include,but are not limited to, methylthio, ethylthio, propylthio, butylthio,cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, andthe like.

As used herein, “arylthio” refers to an —S-aryl or an —S-heteroarylgroup. Representative examples include, but are not limited to,phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio,and the like.

As used herein, “halo” or “halogen” refers to fluorine, chlorine,bromine or iodine.

As used herein, “cyano” refers to a —CN group.

The term “oxo” represents a carbonyl oxygen. For example, a cyclopentylsubstituted with oxo is cyclopentanone.

As used herein, “bond” refers to a covalent bond.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. Where the term “substituted” isused to describe a structural system, the substitution is meant to occurat any valency-allowed position on the system. In some embodiments,“substituted” means that the specified group or moiety bears one, two,or three substituents. In other embodiments, “substituted” means thatthe specified group or moiety bears one or two substituents. In stillother embodiments, “substituted” means the specified group or moietybears one substituent.

As used herein, “optional” or “optionally” means that the subsequentlydescribed event or circumstance may but need not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, “wherein each hydrogenatom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3-to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by C₁-C₆ alkyl” meansthat an alkyl may be but need not be present on any of the C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl byreplacement of a hydrogen atom for each alkyl group, and the descriptionincludes situations where the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, ormono- or bicyclic heteroaryl is substituted with an alkyl group andsituations where the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- orbicyclic heteroaryl is not substituted with the alkyl group.

As used herein, “independently” means that the subsequently describedevent or circumstance is to be read on its own relative to other similarevents or circumstances. For example, in a circumstance where severalequivalent hydrogen groups are optionally substituted by another groupdescribed in the circumstance, the use of “independently optionally”means that each instance of a hydrogen atom on the group may besubstituted by another group, where the groups replacing each of thehydrogen atoms may be the same or different. Or for example, wheremultiple groups exist all of which can be selected from a set ofpossibilities, the use of “independently” means that each of the groupscan be selected from the set of possibilities separate from any othergroup, and the groups selected in the circumstance may be the same ordifferent.

As used herein, the phrase “taken together with the carbon to which theyare attached” or “taken together with the carbon atom to which they areattached” means that two substituents (e.g. R¹ and R²) attached to thesame carbon atom form the groups that are defined by the claim, such asC₃-C₆ cycloalkyl or a 4- to 6-membered heterocycloalkyl. In particular,the phrase “taken together with the carbon to which they are attached”means that when, for example, R¹ and R², and the carbon atom to whichthey are attached form a C₃-C₆ cycloalkyl, then the formed ring will beattached at the same carbon atom. For example, the phrase “R¹ and R²taken together with the carbon to which they are attached form a C₃-C₆cycloalkyl” used in connection with the embodiments described hereinincludes fragments represented as follows:

where the above spirocyclic rings can be optionally substituted asdefined in a given embodiment.

As used herein, the phrase “taken together with the carbons to whichthey are attached” or “taken together with the carbon atoms to whichthey are attached” means that two substituents (e.g. R¹ and R²) attachedto different carbon atoms form the groups that are defined by the claim,such as C₃-C₆ cycloalkyl or a 4- to 6-membered heterocycloalkyl. Inparticular, the phrase “taken together with the carbons to which theyare attached form a” means that when, for example, R¹ and R², and thecarbon atoms, which are not the same carbon atom, to which they areattached form a C₃-C₆ cycloalkyl, then the formed ring will be attachedat different carbon atoms. For example, the phrase “R¹ and R² takentogether with the carbons to which they are attached form a C₃-C₆cycloalkyl” used in connection with the embodiments described hereinincludes fragments represented as follows:

where the above fused rings can be optionally substituted as defined ina given embodiment. Likewise, the phrase “R⁷ and R⁸ combine to form aC₃-C₇ cycloalkyl, a 5- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or5- to 7-membered heteroaryl” also means that R⁷ and R⁸ are takentogether with the carbon atoms to which they are attached to form aC₃-C₇ cycloalkyl, a 5- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or5- to 7-membered heteroaryl. In particular, “R⁷ and R⁸ combine to form aC₃-C₇ cycloalkyl” used in connection with the embodiments describedherein includes fragments represented by the following:

where the above fused rings can be optionally substituted as defined ina given embodiment. One of skill in the art will appreciate that allstereochemical arrangements are included within the structures providedabove, such as with respect to the five-carbon ring formed by R⁷ and R⁸as provided in the following fragments:

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which counter ions which may be used in pharmaceuticals.See, generally, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm.Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts arethose that are pharmacologically effective and suitable for contact withthe tissues of subjects without undue toxicity, irritation, or allergicresponse. A compound described herein may possess a sufficiently acidicgroup, a sufficiently basic group, both types of functional groups, ormore than one of each type, and accordingly react with a number ofinorganic or organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. Such salts include:

(1) acid addition salts, which can be obtained by reaction of the freebase of the parent compound with inorganic acids such as hydrochloricacid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, andperchloric acid and the like, or with organic acids such as acetic acid,oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaricacid, citric acid, succinic acid or malonic acid and the like; or

(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicbase such as ethanolamine, diethanolamine, triethanolamine,trimethamine, N-methylglucamine, and the like.

Pharmaceutically acceptable salts are well known to those skilled in theart, and any such pharmaceutically acceptable salt may be contemplatedin connection with the embodiments described herein. Examples ofpharmaceutically acceptable salts include sulfates, pyrosulfates,bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates,dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,bromides, iodides, acetates, propionates, decanoates, caprylates,acrylates, formates, isobutyrates, caproates, heptanoates, propiolates,oxalates, malonates, succinates, suberates, sebacates, fumarates,maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates,chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates,methoxybenzoates, phthalates, sulfonates, methylsulfonates,propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates,tartrates, and mandelates. Lists of other suitable pharmaceuticallyacceptable salts are found in Remington's Pharmaceutical Sciences, 17thEdition, Mack Publishing Company, Easton, Pa., 1985.

For a compound of Formula I, II, III, IV or V that contains a basicnitrogen, a pharmaceutically acceptable salt may be prepared by anysuitable method available in the art, for example, treatment of the freebase with an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoricacid, and the like, or with an organic acid, such as acetic acid,phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbicacid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid,valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, apyranosidyl acid, such as glucuronic acid or galacturonic acid, analpha-hydroxy acid, such as mandelic acid, citric acid, or tartaricacid, an amino acid, such as aspartic acid or glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, orany compatible mixture of acids such as those given as examples herein,and any other acid and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology.

The disclosure also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula I, II, III, IV or V, and treatment methodsemploying such pharmaceutically acceptable prodrugs. The term “prodrug”means a precursor of a designated compound that, followingadministration to a subject, yields the compound in vivo via a chemicalor physiological process such as solvolysis or enzymatic cleavage, orunder physiological conditions (e.g., a prodrug on being brought tophysiological pH is converted to the compound of Formula I, II, III, IVor V). A “pharmaceutically acceptable prodrug” is a prodrug that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to the subject. Illustrative procedures for theselection and preparation of suitable prodrug derivatives are described,for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

The present disclosure also relates to pharmaceutically activemetabolites of compounds of Formula I, II, III, IV or V, and uses ofsuch metabolites in the methods of the disclosure. A “pharmaceuticallyactive metabolite” means a pharmacologically active product ofmetabolism in the body of a compound of Formula I, II, III, IV or V, orsalt thereof. Prodrugs and active metabolites of a compound may bedetermined using routine techniques known or available in the art. See,e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al.,J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34,220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design ofProdrugs (Elsevier Press, 1985); and Larsen, Design and Application ofProdrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds.,Harwood Academic Publishers, 1991).

Any formula depicted herein is intended to represent a compound of thatstructural formula as well as certain variations or forms. For example,a formula given herein is intended to include a racemic form, or one ormore enantiomeric, diastereomeric, or geometric isomers, or a mixturethereof. Additionally, any formula given herein is intended to referalso to a hydrate, solvate, or polymorph of such a compound, or amixture thereof. For example, it will be appreciated that compoundsdepicted by a structural formula containing the symbol “

” include both stereoisomers for the carbon atom to which the symbol “

” is attached, specifically both the bonds “

” and “

” are encompassed by the meaning of “

”. For example, in some exemplary embodiments, certain compoundsprovided herein can be described by the formula

which formula will be understood to encompass compounds having bothstereochemical configurations at the relevant carbon atom, specificallyin this example

and other stereochemical combinations.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labelled compoundsare useful in metabolic studies (preferably with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques[such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT)] including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Further,substitution with heavier isotopes such as deuterium (i.e., ²H) mayafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements. Isotopically labeled compounds of this disclosure andprodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B—, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the secondsubstituted member and B attached to the first substituted member.

REPRESENTATIVE EMBODIMENTS

In some embodiments, compounds described herein comprise a moiety of theformula

wherein Z¹-Z⁶ and Y are defined as described herein, and thesubstituents on the non-aromatic ring marked by a bond and ˜ correspondto R⁷ and R⁸ as described herein. In other embodiments, compoundsdescribed herein comprise a moiety of the formula

wherein Z¹-Z⁶, R⁹, and R¹⁰ are otherwise defined as described herein,and the substituents on the non-aromatic ring marked by a bond and ˜correspond to R⁷ and R⁸ as described herein. In still other embodiments,compounds described herein comprise a moiety of the formula

wherein Z¹-Z⁶ and Y are otherwise defined as described herein, and thesubstituents on the non-aromatic ring marked by a bond and ˜ correspondto R⁷ and R⁸ as described herein. In some embodiments, each of Z¹, Z²,Z³, Z⁴, Z⁵, and Z⁶ is independently N, NH, C or CH. In some embodiments,Z¹, Z³ and Z⁶ are N, Z² and Z⁵ are CH, and Z⁴ is C. In some embodiments,Z¹, Z³ and Z⁶ are N, Z² and Z⁵ are CH, Z⁴ is C, and Y is O. In someembodiments, Z¹, Z² and Z⁶ are N, Z⁵ is CH, and Z³ and Z⁴ are C. In someembodiments, Z¹, Z² and Z⁶ are N, Z⁵ is CH, Z³ and Z⁴ are C, and Y is O.In some embodiments, Z², Z and Z⁵ are N, Z and Z⁶ are CH, and Z³ is C.In some embodiments, Z², Z⁴ and Z⁵ are N, Z¹ and Z⁶ are CH, Z³ is C andY is O. In some embodiments, Z¹, Z⁴ and Z⁶ are N, Z² and Z⁵ are CH, andZ³ is C. In some embodiments, Z¹, Z⁴ and Z⁶ are N, Z² and Z⁵ are CH, Z³is C, and Y is O. In some embodiments, Z² and Z⁴ are N, Z⁶, Z⁵ and Z⁶are CH, and Z³ is C. In some embodiments, Z² and Z⁴ are N, Z¹, Z⁵ and Z⁶are CH, Z³ is C, and Y is O.

In still other embodiments, compounds described herein comprise a moietyof the formula

wherein Y is otherwise defined as described herein, and the substituentson the non-aromatic ring marked by a bond and ˜ correspond to R⁷ and R⁸as described herein. In still other embodiments, compounds describedherein comprise a moiety of the formula

wherein Y is otherwise defined as described herein. In still otherembodiments, compounds described herein comprise a moiety of the formula

In still other embodiments, compounds described herein comprise a moietyof the formula

In still other embodiments, compounds described herein comprise a moietyof the formula

In still other embodiments, compounds described herein comprise a moietyof the formula

In some embodiments, L is —C(R¹)(R²)—. In some embodiments, L is X. Insome embodiments, when t is 1, L is —C(R¹)(R²)—.

In some embodiments, X is —O—. In some embodiments, X is —S—. In someembodiments, X is —S(O)—. In some embodiments, X is —S(O)₂. In someembodiments, when t is 1, L is not X. In some embodiments, when t is 2,2, or 4, the L attached directly to the amide nitrogen in the macrocycleis not X.

In some embodiments, each R¹ and R² is independently H, deuterium,halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3-to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl, —OR^(a), —OC(O)R^(a), —OC(O)R^(a), —OC(O)NR^(a)R^(b),—OS(O)R^(a), —OS(O)₂R^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —OS(O)NR^(a)R^(b),—OS(O)₂NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b),—NR^(a)C(O)NR^(a)R^(b), —NR^(a)S(O)R^(b), —NR^(a)S(O)₂R^(b),—NR^(a)S(O)NR^(a)R^(b), —NR^(a)S(O)₂NR^(a)R^(b), —C(O)R^(a),—C(O)OR^(a), —C(O)NR^(a)R^(b), —PR^(a)R^(b), —P(O)R^(a)R^(b),—P(O)₂R^(a)R^(b), —P(O)NR^(a)R^(b), —P(O)₂NR^(a)R^(b), —P(O)OR^(a),—P(O)₂OR^(a), —CN, or —NO₂, or R¹ and R² taken together with the carbonor carbons to which they are attached form a C₃-C₆ cycloalkyl or a 4- to6-membered heterocycloalkyl, wherein each hydrogen atom in C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, mono- or bicyclic heteroaryl, 4- to6-membered heterocycloalkyl is independently optionally substituted bydeuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OR^(e), —OC(O)R^(e),—OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f), —NR^(e)R^(f), —NR^(e)C(O)R^(f),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(t),—NR^(e)S(O)₂R^(t), —NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f),—C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f),—P(O)R^(e)R^(f), —P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f),—P(O)OR^(e), —P(O)₂OR^(e), —CN, or —NO₂.

In some embodiments, R¹ and R² are each independently H, deuterium,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀aryl, —OR^(a), —SR^(a), —NR^(a)R^(b), —C(O)OR^(a), —C(O)NR^(a)R^(b);wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independently optionally substitutedby deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —OC₁-C₆ alkyl(C₆-C₁₀aryl), —NH₂, —OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆ alkyl)₂, —OC(O)NH(C₁-C₆alkyl), —OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂, —OC(═N)NH(C₁-C₆ alkyl),—OC(═N)NH₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆ alkyl, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆ alkyl)C(O)OH, —NHS(O)C₁-C₆alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂,—N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂,—C(O)C₁-C₆ alkyl, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl,—S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)NH₂, —S(O)₂NH₂,—OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂N(C₁-C₆ alkyl)₂, —OS(O)NH(C₁-C₆ alkyl),—OS(O)₂NH(C₁-C₆ alkyl), —OS(O)NH₂, —OS(O)₂NH₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl.

In some embodiments, R¹ is H. In some embodiments, R² is H. In someembodiments, R¹ is C₁-C₆ alkyl. In some embodiments, R¹ is methyl. Insome embodiments, R¹ is C₃-C₆ cycloalkyl. In some embodiments, R¹ iscyclopropyl. In some embodiments, R² is C₁-C₆ alkyl. In someembodiments, R² is methyl. In some embodiments, R² is C₃-C₆ cycloalkyl.In some embodiments, R² is cyclopropyl. In some embodiments, R¹ is H andR² is C₁-C₆ alkyl. In some embodiments, R¹ and R² taken together withthe carbon or carbons to which they are attached form a C₃-C₆cycloalkyl. In some embodiments, R¹ and R² taken together with thecarbon or carbons to which they are attached form a cyclopropane ring.

In some embodiments, M is CR³. In some embodiments, M is N. In someembodiments, M¹ is CR⁴.

In some embodiments, each R³, R⁴, and R⁵ is independently hydrogen,deuterium, halogen, —OR^(c), —OC(O)R^(c), —OC(O)NR^(e)R^(d),—OC(═N)NR^(e)R^(d), —OS(O)R^(c), —OS(O)₂R^(c), —OS(O)NR^(e)R^(d),—OS(O)₂NR^(e)R^(d), —SR^(c), —S(O)R^(c), —S(O)₂R^(c), —S(O)NR^(e)R^(d),—S(O)₂NR^(e)R^(d), —NR^(e)R^(d), —NR^(c)C(O)R^(d), —NR^(c′)C(O)OR^(d),—NR^(c)C(O)NR^(c)R^(d), —NR^(c)C(═N)NR^(c)R^(d), —NR^(c)S(O)R^(d),—NR^(c)S(O)₂R^(d), —NR^(c)S(O)NR^(c)R^(d), —NR^(c)S(O)₂NR^(c)R^(d),—C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(d), —C(═N)NR^(c)R^(d),—PR^(c)R^(d), —P(O)R^(c)R^(d), —P(O)₂R^(c)R^(d), —P(O)NR^(c)R^(d),—P(O)₂NR^(c)R^(d), —P(O)OR^(c), —P(O)₂OR^(c), —CN, —NO₂, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, or R⁴and R⁵ taken together with the ring to which they are attached form aC₅-C₈ cycloalkyl, or a 5- to 8-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, mono- orbicyclic heteroaryl, C₅-C₈ cycloalkyl, or 5- to 8-memberedheterocycloalkyl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OR^(e), —OC(O)R^(e),—OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f), —NR^(e)R^(f), —NR^(e)C(O)R^(t),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f),—NR^(e)S(O)₂R^(f), —NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f),—C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f),—P(O)R^(e)R^(f), —P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f),—P(O)OR^(e), —P(O)₂OR^(e), —CN, or —NO₂. In some embodiments, each R³,R⁴, and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃. Insome embodiments, R³ is H, deuterium, C₁-C₆ alkyl or halogen. In someembodiments, R³ is H or F. In some embodiments, R⁴ is H, deuterium,C₁-C₆ alkyl or halogen. In some embodiments, R⁴ is H or Cl. In someembodiments, R⁵ is F.

In some embodiments, R⁶ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl,C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atomin C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by deuterium,halogen, —OR^(e), —OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f),—OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f), —NR^(e)S(O)₂R^(f),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e),—P(O)₂OR^(e), —CN, or —NO₂. In some embodiments, R⁶ is H, C₁-C₆ alkyl or3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C₁-C₆alkyl or 3- to 7-membered heterocycloalkyl is independently optionallysubstituted by halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or monocyclic 5- to7-membered heterocycloalkyl.

In some embodiments, R⁷ and R⁸ combine to form a C₃-C₇ cycloalkyl, a 5-to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-memberedheteroaryl; wherein each hydrogen atom in C₃-C₇ cycloalkyl, a 5- to8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, —OR^(e),—OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e),—S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(t), —NR^(e)C(O)OR^(t),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(t), —NR^(e)S(O)₂R^(t),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e),—P(O)₂OR^(e), —CN, or —NO₂.

In some embodiments, R⁷ and R⁸ combine to form a C₃-C₇ cycloalkyl, a 5-to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-memberedheteroaryl; wherein each hydrogen atom in C₃-C₇ cycloalkyl, a 5- to8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, —OH,—OC₁-C₆ alkyl, —OC(O)C₁-C₆ alkyl, —OC(O)NH₂, —OC(O)NH(C₁-C₆ alkyl),—OC(O)N(C₁-C₆ alkyl)₂, —OC(═N)NH₂, —OC(═N)NH(C₁-C₆ alkyl),—OC(═N)N(C₁-C₆ alkyl)₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆ alkyl,—OS(O)NH₂, —OS(O)NH(C₁-C₆ alkyl), —OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂NH₂,—OS(O)₂NH(C₁-C₆ alkyl), —OS(O)₂N(C₁-C₆ alkyl)₂, —SH, —SC₁-C₆ alkyl,—S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH₂, —S(O)NH(C₁-C₆ alkyl),—S(O)(C₁-C₆ alkyl)₂, —S(O)₂NH₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂N(C₁-C₆alkyl)₂, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)OH, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OH, —N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH₂,—N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂,—NHS(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —NHS(O)₂C₁-C₆ alkyl,—N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂NH₂, —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —C(O)C₁-C₆ alkyl, —C(O)OC₁-C₆ alkyl,—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, —P(O)₂(C₁-C₆ alkyl)₂, —P(O)NH₂, —P(O)NH(C₁-C₆alkyl), —P(O)N(C₁-C₆ alkyl)₂, —P(O)₂NH₂, —P(O)₂NH(C₁-C₆ alkyl),—P(O)₂N(C₁-C₆ alkyl)₂, —P(O)OH, —P(O)OC₁-C₆ alkyl, —P(O)₂OH,—P(O)₂OC₁-C₆ alkyl, —CN, or —NO₂.

In some embodiments, R⁷ and R⁸ combine to form a 5- or 6-memberedcycloalkyl, wherein each hydrogen atom in the 4-, 5- or 6-memberedcycloalkyl is independently optionally substituted by deuterium,halogen, —OH, —CN, —OC₁-C₆ alkyl, —OC₁-C₆ alkyl(C₆-C₁₀ aryl), —NH₂,—OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆ alkyl)₂, —OC(O)NH(C₁-C₆ alkyl),—OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂, —OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂,—OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆ alkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂,—NHC(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆ alkyl)C(O)OH, —NHS(O)C₁-C₆alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂,—N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂,—C(O)C₁-C₆ alkyl, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl,—S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)NH₂, —S(O)₂NH₂,—OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂N(C₁-C₆ alkyl)₂, —OS(O)NH(C₁-C₆ alkyl),—OS(O)₂NH(C₁-C₆ alkyl), —OS(O)NH₂, —OS(O)₂NH₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl.

In some embodiments, R⁷ and R⁸ combine to form a 3-, 4-, 5- or6-membered heterocycloalkyl, wherein each hydrogen atom in the 3-, 4-,5- or 6-membered heterocycloalkyl is independently optionallysubstituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —OC₁-C₆alkyl(C₆-C₁₀ aryl), —NH₂, —OC(O)C₁-C₆ alkyl, —OC(O)N(C₁-C₆ alkyl)₂,—OC(O)NH(C₁-C₆ alkyl), —OC(O)NH₂, —OC(═N)N(C₁-C₆ alkyl)₂,—OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂, —OS(O)C₁-C₆ alkyl, —OS(O)₂C₁-C₆alkyl, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl,—N(C₁-C₆ alkyl)C(O)OC₁-C₆ alkyl, —NHC(O)OH, —N(C₁-C₆ alkyl)C(O)OH,—NHS(O)C₁-C₆ alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl,—N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)NH₂, —NHS(O)₂NH₂, —N(C₁-C₆alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —C(O)C₁-C₆ alkyl, —CO₂H, —C(O)OC₁-C₆ alkyl,—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl,—S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl),—S(O)₂NH(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)NH₂, —S(O)₂NH₂, —OS(O)N(C₁-C₆ alkyl)₂, —OS(O)₂N(C₁-C₆ alkyl)₂,—OS(O)NH(C₁-C₆ alkyl), —OS(O)₂NH(C₁-C₆ alkyl), —OS(O)NH₂, —OS(O)₂NH₂,—P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to7-membered heterocycloalkyl. In some embodiments, R⁷ and R⁸ combine toform a tetrahydrofuran ring. In some embodiments, R⁷ and R⁸ combine toform a cyclopentane ring.

In some embodiments, Y is —O—, —S—, —NR⁹, or —CR⁹R¹⁰—. In someembodiments, Y is —O—.

In some embodiments, R⁹ and R¹⁰ are each independently H, deuterium,halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3-to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl, wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl,C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl is optionally substitutedby a halogen, —OR^(e), —OC(O)R^(e), —OC(O)NR^(e)R^(f),—OC(═N)NR^(e)R^(f), —OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(e)R^(f),—OS(O)₂NR^(e)R^(f), —SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f),—S(O)₂NR^(e)R^(f), —NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(t), —NR^(e)S(O)₂R^(t),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e), or—P(O)₂OR^(e).

In some embodiments, R⁹ and R¹⁰ are each independently H, deuterium,halogen, or C₁-C₆ alkyl, wherein each hydrogen atom in C₁-C₆ alkyl isoptionally substituted by a halogen, —OH, —OC₁-C₆ alkyl, —OC(O)C₁-C₆alkyl, —OC(O)N(C₁-C₆ alkyl)₂, —OC(O)NH(C₁-C₆ alkyl), —OC(O)NH₂,—OC(═N)N(C₁-C₆ alkyl)₂, —OC(═N)NH(C₁-C₆ alkyl), —OC(═N)NH₂, —OS(O)C₁-C₆alkyl, —OS(O)₂C₁-C₆ alkyl, —OS(O)N(C₁-C₆ alkyl)₂, —OS(O)NH(C₁-C₆ alkyl),—OS(O)NH₂, —OS(O)₂N(C₁-C₆ alkyl)₂, —OS(O)₂NH(C₁-C₆ alkyl), —OS(O)₂NH₂,—SH, —SC₁-C₆ alkyl, —S(O)C₁-C₆ alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)N(C₁-C₆alkyl)₂, —S(O)NH(C₁-C₆ alkyl), —S(O)NH₂, —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)₂NH(C₁-C₆ alkyl), —S(O)₂NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl),—NH₂, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)OH, —NHC(O)OC₁-C₆ alkyl,—NHC(O)OH, —N(C₁-C₆ alkyl)C(O)N(C₁C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁C₆alkyl), —N(C₁-C₆ alkyl)C(O)NH₂, —NHC(O)N(C₁C₆ alkyl)₂, —NHC(O)NH(C₁C₆alkyl), —NHC(O)NH₂, —N(C₁-C₆ alkyl)S(O)C₁-C₆ alkyl, —NHS(O)C₁-C₆ alkyl,—N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)NH₂, —NHS(O)N(C₁-C₆ alkyl)₂, —NHS(O)NH(C₁-C₆ alkyl),—NHS(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂NH₂, —NHS(O)₂N(C₁-C₆alkyl)₂, —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)₂NH₂, —C(O)C₁-C₆ alkyl,—C(O)OC₁-C₆ alkyl, —C(O)N(C₁-C₆ alkyl)z, —C(O)NH(C₁-C₆ alkyl), —C(O)NH₂,—P(C₁-C₆ alkyl)z, —P(O)(C₁-C₆ alkyl)z, —P(O)₂(C₁-C₆ alkyl)₂,—P(O)N(C₁-C₆ alkyl)z, —P(O)₂N(C₁-C₆ alkyl)z, —P(O)OC₁-C₆ alkyl, or—P(O)₂OC₁-C₆ alkyl.

In some embodiments, each R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f)is independently selected from the group consisting of H, deuterium,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 7-membered heteroaryl.

In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1.

In some embodiments, t is 1, 2, 3, 4, or 5. In some embodiments, t is 3.In some embodiments, t is 4. In some embodiments, t is 3 or 4.

In some embodiments, n, if present, is 1, 2, or 3. In some embodiments,n is 2. In some embodiments, n is 3. In some embodiments, n is 2 or 3.

The following represent illustrative embodiments of compounds of theformula I, II, III, and IV:

Compound Structure Name  1

(3aR,11S,20aS)-7-fluoro-11-methyl-2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-(metheno)cyclopenta[5,6][l,4]oxazino[3,4- i]pyrazolo[4,3-f[1,4,8,10]benzoxatriazacyclotridecin- 14(11H)-one  2

(7S)-3-amino-11-fluoro-7-methyl-4-oxo-14-(propan-2-yl)-4,5,6,7,13,14-hexahydro-1,15- ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-12- carbonitrile  3

(3aR,11S,20aS)-7,9-difluoro-11-methyl-2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin- 14(11H)-one  4

(3aR,11S,20aR)-7-fluoro-11-methyl- 1,3,3a,12,13,20a-hexahydro-5H-17,19-(metheno)furo[3′,4′:5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin- 14(11H)-one  5

(3aR,11S,20aS)-7-fluoro-11-methyl-2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin- 14(11H)-one  6

(3aR,12R,20aS)-7-fluoro-12-methyl-2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin- 14(11H)-one  7

(3aR,12R,20aS)-7,9-difluoro-12-methyl-2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin- 14(11H)-one  8

(2aR,10S,19aS)-6-fluoro-10-methyl- 1,2,2a,11,12,19a-hexahydro-4H-16,18-(metheno)cyclobuta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin- 13(10H)-one  9

(2aS,10S,19aR)-6-fluoro-10-methyl- 1,2,2a,11,12,19a-hexahydro-4H-16,18-(metheno)cyclobuta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin- 13(10H)-one 10

(2aR,11R,19aS)-6-fluoro-11-methyl- 1,2,2a,11,12,19a-hexahydro-4H-16,18-(metheno)cyclobuta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin- 13(10H)-one 11

(2aS,11R,19aR)-6-fluoro-11-methyl- 1,2,2a,11,12,19a-hexahydro-4H-16,18-(metheno)cyclobuta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin- 13(10H)-one 12

(4aR,12S,21aS)-8-fluoro-12-methyl-1,2,3,4,4a,13,14,21a-octahydro-6H-18,20-(metheno)pyrazolo[4′,3′:6,7]pyrido[3′,2′:12,l3][1,4,8,10]oxatriazacyclotridecino[9,10- c][1,4]benzoxazin-15(12H)-one13

(4aR,13R,21aS)-8-fluoro-13-methyl-1,2,3,4,4a,13,14,21a-octahydro-6H-18,20-(metheno)pyrazolo[4′,3′:6,7]pyrido[3′,2′:12,13][1,4,8,10]oxatriazacyclotridecino[9,10- c][1,4]benzoxazin-15(12H)-one14

(3aR,12R,20aS)-12-cyclopropyl-7-fluoro-2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-(metheno)cyclobuta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin- 13(10H)-one 15

(3aR,11S,21aS)-7-fluoro-11-methyl- 2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20- (metheno)cyclobuta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin-15-one16

(3aR,13R,21aS)-7-fluoro-13-methyl- 2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20- (metheno)cyclobuta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin-15-one17

(3aR,12S,21aS)-7-fluoro-12-methyl- 2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin-15-one18

(3a′R,20a′S)-7′-fluoro- 1′H,2′H,3′H,3a′H,5′H,11′H,13′H,14′H,20a′H,spiro[cyclopropane-1,12′-[10,20]dioxa[4,9,13,16,17,18]hexaaza[17,19](metheno)cyclopenta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin]-14′-one 19

(3aR,21aS)-7-fluoro-2,3,3a,11,12,13,14,21a- octahydro-1H,5H,15H-18,20-(metheno)cyclopenta[5,6][1,4]oxazino[4,3- e]pyrazolo[3,4-h]pyrido[2,3-b][1,5,7,11]oxatriazacyclotetradecin-15-one 20

(3a′R,21a′S)-7′-fluoro- 1′H,2′H,3′H,3a′H,5′H,11′H,13′H,14′H,15′H,21a′H,spiro[cyclopropane-1,12′-[10,21]dioxa[4,9,14,17,18,19]hexaaza[18,20](metheno)cyclopenta[5,6][1,4]oxazino[4,3- e]pyrazolo[3,4-h]pyrido[2,3-b][1,5,7,11]oxatriazacyclotetradecin]- 15′-one 21

(3aR,20aS)-7-fluoro-12,12-dimethyl-2,3,3a,12,13,20a-hexahydro-1H,5H,17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin- 14(11H)-one 22

(3a′R,20a′S)-7′-fluoro- 1′H,2′H,3′H,3a′H,5′H,11′H,13′H,14′H,20a′H-spiro[cyclobutane-1,12′- [10,20]dioxa[4,9,13,16,17,18]hexaaza[17,19](metheno)cyclopenta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f]pyrido[3,2-i][1,4,8,10]oxatriazacyclotridecin]-14′-oneo 23

(3a′R,21a′S)-7′-fluoro- 1′H,2′H,3′H,3a′H,5′H,11′H,13′H,14′H,15′H,21a′H-spiro[cyclobutane-1,12′-[10,21]dioxa[4,9,14,17,18,19]hexaaza[18,20](metheno)cyclopenta[5,6][1,4]oxazino[4,3- e]pyrazolo[3,4-h]pyrido[2,3-b][1,5,7,11]oxatriazacyclotetradecin]- 15′-one 24

(3aS,11aR,14aS,21aR)-18-fluoro-2,3,3a,11,11a,12,13,14,14a,21a-decahydro- 1H,10H,20H-7,5-(metheno)cyclopenta[b]cyclopenta[5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-10-one 25

(3a′R,20a′S)-3,3,7′-trifluoro-1′H,2′H,3′H,3a′H,5′H,11′H,13′H,14′H,20a′H- spiro[cyclobutane-1,12′-[10,20]dioxa[4,9,13,16,17,18]hexaaza[17,19](metheno)cyclopenta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin]-14′-one 26

(3a′R,20a′S)-7′-fluoro- 1′H,2′H,3′H,3a′H,5′H,11′H,13′H,14′H,20a′H-spiro[cyclobutane-1,12′- [10,20]dioxa[4,9,13,16,17,18]hexaaza[17,19](metheno)cyclopenta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin]-14′-one 27

(3aR,21aS)-7-fluoro-12,12-dimethyl- 2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20- (metheno)cyclobuta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin-15-one28

(3aR,13S,21aS)-7-fluoro-13-methyl- 2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin-15-one29

(3aR,21aS)-7-fluoro-12-methyl- 2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin-15-one30

(3aR,11S,20aR)-7-fluoro-11-methyl- 1,3,3a,12,13,20a-hexahydro-5H-17,19-(metheno)furo[3′,4′:5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-14(11H)- one 31

(3aS,11S,20aS)-7-fluoro-11-methyl- 1,3,3a,12,13,20a-hexahydro-5H-17,19-(metheno)furo[3′,4′:5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-14(11H)-one 32

(3aR,12S,21aS)-7-fluoro-12-hydroxy-2,3,3a,11,12,13,14,21a-octahydro-1H,5H, 15H-18,20-(metheno)cyclopenta[5,6][1,4]oxazino[4,3- e]pyrazolo[3,4-h]pyrido[2,3-b][1,5,7,11]oxatriazacyclotetradecin-15-one 33

(3aR,21aS)-7-fluoro-12,12-dihydroxy- 2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20-(metheno)cyclopenta [5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin-15-one34

(3aR,21aS)-7-fluoro-13,13-dimethyl- 2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20-(metheno)cyclopenta [5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin-15-one 35

(3aR,11R,21aS)-7-fluoro-11-methyl- 2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20-(metheno)cyclopenta [5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin-15-one 36

(3aR,11S,20aS)-2-acetyl-7-fluoro-11-methyl-2,3,3a,11,12,13,20a-hexahydro-1H,5H-17,19-(metheno)pyrazolo[4,3-f]pyrido[2,3-l]pyrrolo[3′,4′:5,6][1,4] oxazino[3,4-i][1,4,8,10]oxatriazacyclotridecin-14(11H)-one 37

(3aS,11S,20aR)-2-acetyl-7-fluoro-11- methyl-2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-(metheno)pyrazolo[4,3-f]pyrido[3,2-l]pyrrolo[3′,4′:5,6][1,4] oxazino[3,4-i][1,4,8,10]oxatriazacyclotridecin-14(11H)-one 38

(3aR,12S,21aS)-7,12-difluoro- 2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20-(metheno)cyclopenta [5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin-15-one 39

(3aR,12R,21aS)-7,12-difluoro- 2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20-(metheno)cyclopenta [5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin-15-one40

(3aR,21aS)-7,12,12-trifluoro- 2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20-(metheno)cyclopenta [5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin-15-one41

(3aR,11R,14S,22aS)-7-fluoro- 2,3,3a,12,13,14,15,22a-octahydro-1H,5H,11,14-methano-19,21- (metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclopentadecin-16(11H)-one 42

(3aR,11S,14R,22aS)-7-fluoro- 2,3,3a,12,13,14,15,22a-octahydro-1H,5H,11,14-methano-19,21- (metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclopentadecin-16(11H)-one 43

(3aR,12R,21aS)-7-fluoro-12-hyroxy- 2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20-(metheno)cyclopenta [5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin-15-one44

(3aS,11R,20aR)-7-fluoro-11-methyl- 2,3,3a,12,13,20a-hexahydro-1H,5H,17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-14(11H)-one 45

(3a′R,21a′S)-7′-fluoro- 1′H,2′H,3′H,3a′H,5′H,11′H,12′H,14′H,15′H,21a′H-spiro[cyclobutane-1,13′-[10,21]dioxa[4,9,14,17,18,19]hexaaza[18,20](metheno)cyclopenta[5,6][1,4]oxazino[4,3- e]pyrazolo[3,4-h]pyrido[2,3-b][1,5,7,11]oxatriazacyclotetradecin]-15′-one 46

(3aR,11s,13S,21aS)-7-fluoro- 2,3,3a,12,13,14,15,21a-octahydro-1H,5H,11H-11,13-metheno-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecine 47

(3aR,12S,20aS)-12-difluoromethyl-7- fluoro-2,3,3a,12,13,20a-hexahydro-1H,5H,17,19-(metheno) cyclopenta[5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-14(11H)-one 48

(3aR,12S,20aS)-7-fluoro-12- (trifluoromethyl)-2,3,3a,12,13,20a-hexahydro-1H,5H,17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f]pyrido[3,2- b][1,4,8,10]oxatriazacyclotridecin-14(11H)-one 49

(3aR,11S,20aS)-7-fluoro-11- (hydroxymethyl)-2,3,3a,12,13,20a-hexahydro-1H,5H,17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f]pyrido[3,2- l][1,4,8,10]oxatriazacyclotridecin-14(11H)-one

Those skilled in the art will recognize that the species listed orillustrated herein are not exhaustive, and that additional specieswithin the scope of these defined terms may also be selected.

Pharmaceutical Compositions

For treatment purposes, pharmaceutical compositions comprising thecompounds described herein may further comprise one or morepharmaceutically-acceptable excipients. A pharmaceutically-acceptableexcipient is a substance that is non-toxic and otherwise biologicallysuitable for administration to a subject. Such excipients facilitateadministration of the compounds described herein and are compatible withthe active ingredient. Examples of pharmaceutically-acceptableexcipients include stabilizers, lubricants, surfactants, diluents,anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, ortaste-modifying agents. In preferred embodiments, pharmaceuticalcompositions according to the invention are sterile compositions.Pharmaceutical compositions may be prepared using compounding techniquesknown or that become available to those skilled in the art.

Sterile compositions are also contemplated by the invention, includingcompositions that are in accord with national and local regulationsgoverning such compositions.

The pharmaceutical compositions and compounds described herein may beformulated as solutions, emulsions, suspensions, or dispersions insuitable pharmaceutical solvents or carriers, or as pills, tablets,lozenges, suppositories, sachets, dragees, granules, powders, powdersfor reconstitution, or capsules along with solid carriers according toconventional methods known in the art for preparation of various dosageforms. Pharmaceutical compositions of the invention may be administeredby a suitable route of delivery, such as oral, parenteral, rectal,nasal, topical, or ocular routes, or by inhalation. Preferably, thecompositions are formulated for intravenous or oral administration.

For oral administration, the compounds the invention may be provided ina solid form, such as a tablet or capsule, or as a solution, emulsion,or suspension. To prepare the oral compositions, the compounds of theinvention may be formulated to yield a dosage of, e.g., from about 0.1mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mgdaily, or about 250 mg to 1 g daily. Oral tablets may include the activeingredient(s) mixed with compatible pharmaceutically acceptableexcipients such as diluents, disintegrating agents, binding agents,lubricating agents, sweetening agents, flavoring agents, coloring agentsand preservative agents. Suitable inert fillers include sodium andcalcium carbonate, sodium and calcium phosphate, lactose, starch, sugar,glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, andthe like. Exemplary liquid oral excipients include ethanol, glycerol,water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starchglycolate, microcrystalline cellulose, and alginic acid are exemplarydisintegrating agents. Binding agents may include starch and gelatin.The lubricating agent, if present, may be magnesium stearate, stearicacid, or talc. If desired, the tablets may be coated with a materialsuch as glyceryl monostearate or glyceryl distearate to delay absorptionin the gastrointestinal tract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient(s) may be mixed witha solid, semi-solid, or liquid diluent. Soft gelatin capsules may beprepared by mixing the active ingredient with water, an oil, such aspeanut oil or olive oil, liquid paraffin, a mixture of mono anddi-glycerides of short chain fatty acids, polyethylene glycol 400, orpropylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions, or syrups, or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

For parenteral use, including intravenous, intramuscular,intraperitoneal, intranasal, or subcutaneous routes, the agents of theinvention may be provided in sterile aqueous solutions or suspensions,buffered to an appropriate pH and isotonicity or in parenterallyacceptable oil. Suitable aqueous vehicles include Ringer's solution andisotonic sodium chloride. Such forms may be presented in unit-dose formsuch as ampoules or disposable injection devices, in multi-dose formssuch as vials from which the appropriate dose may be withdrawn, or in asolid form or pre-concentrate that can be used to prepare an injectableformulation. Illustrative infusion doses range from about 1 to 1000μg/kg/minute of agent admixed with a pharmaceutical carrier over aperiod ranging from several minutes to several days.

For nasal, inhaled, or oral administration, the inventive pharmaceuticalcompositions may be administered using, for example, a spray formulationalso containing a suitable carrier. The inventive compositions may beformulated for rectal administration as a suppository.

For topical applications, the compounds of the present invention arepreferably formulated as creams or ointments or a similar vehiclesuitable for topical administration. For topical administration, theinventive compounds may be mixed with a pharmaceutical carrier at aconcentration of about 0.1% to about 10% of drug to vehicle. Anothermode of administering the agents of the invention may utilize a patchformulation to effect transdermal delivery.

As used herein, the terms “treat” or “treatment” encompass both“preventative” and “curative” treatment. “Preventative” treatment ismeant to indicate a postponement of development of a disease, a symptomof a disease, or medical condition, suppressing symptoms that mayappear, or reducing the risk of developing or recurrence of a disease orsymptom. “Curative” treatment includes reducing the severity of orsuppressing the worsening of an existing disease, symptom, or condition.Thus, treatment includes ameliorating or preventing the worsening ofexisting disease symptoms, preventing additional symptoms fromoccurring, ameliorating or preventing the underlying systemic causes ofsymptoms, inhibiting the disorder or disease, e.g., arresting thedevelopment of the disorder or disease, relieving the disorder ordisease, causing regression of the disorder or disease, relieving acondition caused by the disease or disorder, or stopping the symptoms ofthe disease or disorder.

The term “subject” refers to a mammalian patient in need of suchtreatment, such as a human.

Exemplary diseases include cancer, pain, neurological diseases,autoimmune diseases, and inflammation. Cancer includes, for example,lung cancer, colon cancer, breast cancer, prostate cancer,hepatocellular carcinoma, renal cell carcinoma, gastric andesophago-gastric cancers, glioblastoma, head and neck cancers,inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma.Pain includes, for example, pain from any source or etiology, includingcancer pain, pain from chemotherapeutic treatment, nerve pain, pain frominjury, or other sources. Autoimmune diseases include, for example,rheumatoid arthritis, Sjogren syndrome, Type I diabetes, and lupus.Exemplary neurological diseases include Alzheimer's Disease, Parkinson'sDisease, Amyotrophic lateral sclerosis, and Huntington's disease.Exemplary inflammatory diseases include atherosclerosis, allergy, andinflammation from infection or injury.

In one aspect, the compounds and pharmaceutical compositions of theinvention specifically target receptor tyrosine kinases, in particularRET. In another aspect, the compounds and pharmaceutical compositions ofthe invention specifically target non-receptor tyrosine kinases, inparticular SRC. In yet another aspect, the compounds and pharmaceuticalcompositions of the invention specifically target receptor tyrosinekinases and non-receptor tyrosine kinases, such as RET and SRC,respectively. Thus, these compounds and pharmaceutical compositions canbe used to prevent, reverse, slow, or inhibit the activity of one ormore of these kinases. In preferred embodiments, methods of treatmenttarget cancer. In other embodiments, methods are for treating lungcancer or non-small cell lung cancer.

In the inhibitory methods of the invention, an “effective amount” meansan amount sufficient to inhibit the target protein. Measuring suchtarget modulation may be performed by routine analytical methods such asthose described below. Such modulation is useful in a variety ofsettings, including in vitro assays. In such methods, the cell ispreferably a cancer cell with abnormal signaling due to upregulation ofRET and/or SRC.

In treatment methods according to the invention, an “effective amount”means an amount or dose sufficient to generally bring about the desiredtherapeutic benefit in subjects needing such treatment. Effectiveamounts or doses of the compounds of the invention may be ascertained byroutine methods, such as modeling, dose escalation, or clinical trials,taking into account routine factors, e.g., the mode or route ofadministration or drug delivery, the pharmacokinetics of the agent, theseverity and course of the infection, the subject's health status,condition, and weight, and the judgment of the treating physician. Anexemplary dose is in the range of about from about 0.1 mg to 1 g daily,or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250mg to 1 g daily. The total dosage may be given in single or divideddosage units (e.g., BID, TID, QID).

Once improvement of the patient's disease has occurred, the dose may beadjusted for preventative or maintenance treatment. For example, thedosage or the frequency of administration, or both, may be reduced as afunction of the symptoms, to a level at which the desired therapeutic orprophylactic effect is maintained. Of course, if symptoms have beenalleviated to an appropriate level, treatment may cease. Patients may,however, require intermittent treatment on a long-term basis upon anyrecurrence of symptoms. Patients may also require chronic treatment on along-term basis.

Drug Combinations

The inventive compounds described herein may be used in pharmaceuticalcompositions or methods in combination with one or more additionalactive ingredients in the treatment of the diseases and disordersdescribed herein. Further additional active ingredients include othertherapeutics or agents that mitigate adverse effects of therapies forthe intended disease targets. Such combinations may serve to increaseefficacy, ameliorate other disease symptoms, decrease one or more sideeffects, or decrease the required dose of an inventive compound. Theadditional active ingredients may be administered in a separatepharmaceutical composition from a compound of the present invention ormay be included with a compound of the present invention in a singlepharmaceutical composition. The additional active ingredients may beadministered simultaneously with, prior to, or after administration of acompound of the present invention.

Combination agents include additional active ingredients are those thatare known or discovered to be effective in treating the diseases anddisorders described herein, including those active against anothertarget associated with the disease. For example, compositions andformulations of the invention, as well as methods of treatment, canfurther comprise other drugs or pharmaceuticals, e.g., other activeagents useful for treating or palliative for the target diseases orrelated symptoms or conditions. For cancer indications, additional suchagents include, but are not limited to, kinase inhibitors, such as EGFRinhibitors (e.g., erlotinib, gefitinib), Raf inhibitors (e.g.,vemurafenib), VEGFR inhibitors (e.g., sunitinib), ALK inhibitors (e.g.,crizotinib) standard chemotherapy agents such as alkylating agents,antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors,platinum drugs, mitotic inhibitors, antibodies, hormone therapies, orcorticosteroids. For pain indications, suitable combination agentsinclude anti-inflammatories such as NSAIDs. The pharmaceuticalcompositions of the invention may additionally comprise one or more ofsuch active agents, and methods of treatment may additionally compriseadministering an effective amount of one or more of such active agents.

Chemical Synthesis

Exemplary chemical entities useful in methods of the description willnow be described by reference to illustrative synthetic schemes fortheir general preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups.

Abbreviations: The examples described herein use materials, includingbut not limited to, those described by the following abbreviations knownto those skilled in the art:

g grams eq equivalents mmol millimoles mL milliliters EtOAc ethylacetate MHz megahertz ppm parts per million δ chemical shift s singlet ddoublet t triplet q quartet quin quintet br broad m multiplet Hz hertzTHF tetrahydrofuran ° C. degrees Celsius PE petroleum ether EA ethylacetate R_(f) retardation factor N normal J coupling constant DMSO-d₆deuterated dimethyl sulfoxide n-BuOH n-butanol DIEAn,n-diisopropylethylamine TMSCl trimethylsilyl chloride min minutes hrhours Me methyl Et ethyl i-Pr isopropyl TLC thin layer chromatography Mmolar Compd# compound number MS mass spectrum m/z mass-to-charge ratioMs methanesulfonyl FDPP pentafluorophenyl diphenylphosphinate Boctert-butyloxycarbonyl TFA trifluoroacetic acid Tos toluenesulfonyl DMAP4-(dimethylamino)pyridine μM micromolar ATP adenosine triphosphate IC₅₀half maximal inhibitory concentration U/mL units of activity permilliliter KHMDS potassium bis(trimethylsilyl)amide DIAD diisopropylazodicarboxylate MeTHF 2-methyltetrahydrofuran MOM methoxymethyl DCMdichloromethane DMF N,N-dimethylformamide DPPA diphenyl phosphoryl azideDBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIPEA N,N-iisopropylethylamineTBAF Tetrabutylammonium Fluoride TEA Triethylamine TBSTert-butyldimethylsilyl

General Method A.

Preparation of tert-butyl{(2S)-2-[4-fluoro-2-({[(1R,2S)-2-hydroxycyclopentyl]amino}methyl)phenoxy]propyl}carbamate(A-1)

Step 1. To an azeotrope dried mixture of A-1-1 (0.9615 g, 5.65 mmol) andA-1-1A (1.19 g, 6.78 mmol) in DCM (3.62 mL) was added PPh₃ (2.22 g, 8.48mmol) The mixture was stirred until everything dissolved. DIAD (1.83 g,9.04 mmol, 1.78 mL) was added very slowly with mixing at 0° C. Thereaction was warmed to 25° C. and stirred for 16 hr. DCM (5 mL) and 2MNaOH solution (20 mL) were added and stirred vigorously for 4 hours. Themixture was extracted with DCM (3×15 mL), dried with Na₂SO₄ andconcentrated under reduced pressure. Flash chromatography (ISCO system,silica 12 g, 0-30% ethyl acetate in hexane) provided A-1-2 (1.35 g,73%).

Step 2. To a solution of A-1-2 (1.35 g, 4.13 mmol) in THF (8.27 mL) at0° C. was added lithium borohydride (720.51 mg, 33.08 mmol) in smallbatches and the mixture was stirred for 1 hr and was removed from thecold bath. The mixture stirred at ambient temperature for 20 hr, thendiluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). Thecombined organic phase was washed with brine and dried over sodiumsulfate. Flash column chromatography (ISCO, silica, 24 g, ethyl acetatein hexanes) afforded A-1-3 (1.08 g, 3.60 mmol, 87.09% yield).

Step 3. DMSO (422.82 mg, 5.41 mmol, 384.38 uL) in DCM (6 mL) was addeddropwise at −78° C. to oxalyl chloride (686.85 mg, 5.41 mmol, 464.09 uL)in DCM (6 mL). The mixture was stirred for 20 minutes and A-1-3 (1.08 g,3.61 mmol) in DCM (6 mL) was added dropwise at −78° C. and stirred for20 minutes followed by addition of TEA (1.83 g, 18.04 mmol, 2.51 mL).The mixture was stirred as temperature increased to ambient temperatureover 18 h. The reaction was quenched with water (10 mL) and the layerswere separated. The aqueous layer was extracted twice more with DCM(2×10 mL). The combined organic layer was washed with brine and driedover sodium sulfate. Flash chromatography (ISCO, 24 g Silica Gold, 0-30%ethyl acetate in hexanes) afforded A-1-4 (460.2 mg, 1.55 mmol, 42.90%yield).

Step 4. A solution of (1S,2R)-2-aminocyclopentanol HCl salt (69 mg, 504μmol), Hunig's Base (196 mg, 0.26 mL, 1.5 mmol) and A-1-4 (150.00 mg,504 μmol) in dry MeOH (2.50 mL) was heated to 65° C. for 1 hr. Thereaction was cooled to room temperature and NaBH₄ (38 mg, 1.0 mmol) wasadded. The mixture was stirred for 2 hr then quenched with water (3 mL)and stirred for 5 min. The mixture was extracted with DCM (3×5 mL),dried with Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (ISCO system, silica (12 g), 25-50% ethyl acetate inhexane) provided A-1 (125.3 mg, 327 μmol, 64.9% yield).

Compound A-2 was prepared according to General Method A using(1R,2R)-2-aminocyclopentanol in step 4.

General Method B.

Preparation of tert-butyl{(2S)-2-[2,4-difluoro-6-({[(1R,2S)-2-hydroxycyclopentyl]amino}methyl)phenoxy]propyl}carbamate(A-3)

Step 1. Added K₂CO₃ (330.00 mg, 2.39 mmol) to A-3-1 (151 mg, 955.08μmol) and A-3-1A (283.27 mg, 1.19 mmol) in DMF (4.78 mL) and heated to50° C. with stirring for 1 hr. The mixture was cooled and diluted withDCM (3 mL), filtered through a syringe filter and concentrated underreduced pressure. Flash chromatography (ISCO system, silica (12 g),0-30% ethyl acetate in hexane) provide A-3-2 (301 mg, 954 μmol, 99%yield).

Step 4. A solution of (1S,2R)-2-aminocyclopentanol HCl salt (104 mg,0.76 μmol) and A-3-2 (200 mg, 634 μmol) in dry MeOH (3.17 mL) was heatedto 65° C. for 1 hour. The reaction was cooled to room temperature andNaBH₄ (72 mg, 1.9 mmol) was added. The mixture was stirred for 2 hoursthen quenched with water (5 mL) and stirred for 5 min. The mixture wasextracted with DCM (3×15 mL), dried with Na₂SO₄ and concentrated underreduced pressure. Flash chromatography (ISCO system, silica (12 g),0-20% methanol in dichloromethane) provided A-3 (108 mg, 270 μmol, 42%yield).

Compound A-4 was prepared according to General Method A using(3R,4R)-4-aminotetrahydrofuran-3-ol in step 4.

Compound A-5 was prepared according to General Method A using5-Fluoro-2-methoxynicotinaldehyde in step 4.

Compound A-6 was prepared according to General Method A using raccis-tert-butyl-3-amino-4-hydroxypyrrolidine-1-carboxylate and5-Fluoro-2-methoxynicotinaldehyde.

MS [M + H] Compd# Structure m/z A-1

383.2 A-2

383.2 A-3

401.2 A-4

385.2 A-5

241.1 A-6

342.1

General Method C.

Preparation of ethyl6-bromo-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (B-1)

Step 1. To a solution of B-1-1 (10.00 g, 47.80 mmol, 1.00 eq.) in aceticacid (100.00 mL) was added bromine (7.64 g, 47.80 mmol, 2.46 mL, 1.00eq.). The mixture was stirred at 180° C. for 6 hr. TLC (petroleumether/ethyl acetate=1/1) showed the starting material was consumedcompletely and one new spot was found. The mixture was quenched by water(30 mL). The mixture was filtered and the cake was concentrated to giveB-1-2 (10.00 g, 34.71 mmol, 72.62% yield) as a white solid: ¹H NMR (400MHz, DMSO-d6) δ: 12.34 (br. s., 1H), 9.25 (s, 1H), 8.15 (s, 1H), 4.28(q, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).

Step 2. To a solution of B-1-2 (6.00 g, 20.97 mmol, 1.00 eq.) inphosphorus oxychloride (60 mL). The mixture was stirred at 120° C. for16 hr. TLC (petroleum ether/ethyl acetate=3/1) indicated the startingmaterial was consumed completely and one new spot was found. Thereaction mixture was filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=10/1 to 1/1) to give B-1 (2.50 g, 8.21mmol, 39.15% yield) as a white solid; ¹H NMR (400 MHz, CDCl₃) δ: 8.94(s, 1H), 8.54 (s, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).

General Method D.

Preparation of(3aR,11S,20aS)-7-fluoro-11-methyl-2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-14(11H)-one(1)

Step 1. To a solution of B-1 (325 mg, 1.07 mmol) and A-1 (408 mg, 1.07mmol) in n-BuOH (5.3 mL) was added Hunig's base (689 mg, 5.3 mmol, 929μL). The mixture was heated to 90° C. for 15 hr. The reaction was cooledand concentrated under reduced pressure. Flash chromatography (ISCOsystem, silica (12 g), 10-50% ethyl acetate in hexane) provided 1-1(197.7 mg, 303 μmol, 28% yield).

Step 2. To a solution of 1-1 (36.6 mg, 48.5 μmol) in DMF (3 mL) wasadded KOt-Pent (1.7 M, 86 μL) in toluene. The reaction stirred at roomtemperature for 1.5 hours. The reaction was cooled to −20° C. andquenched with saturated NH₄Cl sol. (5 mL) then extracted with DCM (3×10mL). Combined extracts were dried with Na₂SO₄ and concentrated underreduced pressure. Flash chromatography (ISCO system, silica (12 g),10-35% ethyl acetate in hexane) provided 1-2 (12.8 mg, 22 μmol, 46%yield).

Step 3. To a solution of 1-2 (12.8 mg, 22 μmol) in MeOH (3 mL) and THF(1 mL) at ambient temperature was added aqueous LiOH solution (2.0 M,1.0 mL). The mixture was heated at 60° C. for 17 hr, cooled to −20° C.then quenched with aqueous HCl solution (2.0 M) to acidic. The mixturewas extracted with DCM (3×5 mL), dried with Na₂SO₄, concentrated underreduced pressure, and dried under high vacuum. The crude material wasdissolved in DCM (4 mL) followed by addition of HCl in 1,4-dioxane (4 M,3 mL). The mixture was stirred at ambient temperature for 1.5 hr,concentrated under reduced pressure, and dried under high vacuum. Thecrude material was dissolved in in DMF (2.0 mL) and DCM (4.0 mL) andHünig's base (185 mg, 1.4 mmol, 250 μL) then FDPP (34.5 mg, 89 μmol) wasadded in one portion. The reaction was stirred for 1.5 hours thenquenched with 2 M Na₂CO₃ solution (5 mL). The mixture was stirred for 5min then extracted with DCM (4×10 mL). Combined extracts were dried withNa₂SO₄ and concentrated under reduced pressure. Flash chromatography(ISCO system, silica (12 g), 0-5% methanol in dichloromethane) provided1 (8.13 mg, 19 μmol, 85% yield).

Compounds 2 through 4 were prepared according to General Method D usingA-2 through A-4 in step 1 respectively.

General Method E.

Preparation of(3aR,11S,20aS)-7-fluoro-11-methyl-2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-14(11H)-one(5)

Step 1. To a solution of B-1 (454 mg, 1.49 mmol) and A-5 (358 mg, 1.49mmol) in t-BuOH (5.0 mL) was added Hunig's base (963 mg, 7.45 mmol, 1.30mL). The mixture was heated to 105° C. for 17 hr. The reaction wascooled and concentrated under reduced pressure. Flash chromatography(ISCO system, silica (12 g), 10-40% ethyl acetate in hexane) provided5-1 (292 mg, 38% yield).

Step 2. To a solution of 5-1 (18.8 mg, 37 μmol) in DMF (3 mL) was addedKOt-Pent (1.7 M, 65 μL) in toluene. The reaction stirred at roomtemperature for 20 hours. The reaction was cooled to −20° C. andquenched with saturated NH₄Cl sol. (5 mL) then extracted with DCM (3×10mL). Combined extracts were dried with Na₂SO₄ and concentrated underreduced pressure. Flash chromatography (ISCO system, silica (12 g), 0-5%methanol in dichloromethane) provided 5-2 (6.2 mg, 39% yield).

Step 3. To a solution of 5-2 (6.2 mg, 14.5 μmol) in EtOH (4 mL) wasadded aqueous HCl solution (4.0 M, 3.0 mL) in 1,4-dioxane. The mixturewas heated at 70° C. for 6 hours. The mixture was cooled, concentratedunder reduced pressure, and dried under high vacuum to provide crude5-3. Compound was used as is.

Step 4. Added K₂CO₃ (14.0 mg, 101 μmol) to 5-3 (6.2 mg, 14.5 μmol) andA-3-1A (17 mg, 73 μmol) in DMF (250 μL) and stirred for 2 hours. Themixture was cooled and quenched with water (5 mL) then extracted withDCM (3×10 mL). Combined extracts were dried with Na₂SO₄ and concentratedunder reduced pressure. Flash chromatography (ISCO system, silica (12g), 20-100% ethyl acetate in hexane) provide 5-4 (6.1 mg, 73% yield).

Step 5. To a solution of 5-4 (6.1 mg, 10.7 μmol) in MeOH (3 mL) and THF(1 mL) at ambient temperature was added aqueous LiOH solution (2.0 M,1.0 mL). The mixture was heated at 60° C. for 16 hr, cooled to −20° C.then quenched with aqueous HCl solution (2.0 M) to acidic. The mixturewas extracted with DCM (3×5 mL), dried with Na₂SO₄, concentrated underreduced pressure, and dried under high vacuum. The crude material wasdissolved in DCM (4 mL) followed by addition of HCl in 1,4-dioxane (4 M,3 mL). The mixture was stirred at ambient temperature for 2 hours,concentrated under reduced pressure, and dried under high vacuum. Thecrude material was dissolved in in DMF (2.0 mL) and DCM (4.0 mL) andHünig's base (185 mg, 1.4 mmol, 250 μL) then FDPP (34.5 mg, 89 μmol) wasadded in one portion. The reaction was stirred for 1 hour then quenchedwith 2 M Na₂CO₃ solution (5 mL). The mixture was stirred for 5 min thenextracted with DCM (4×10 mL). Combined extracts were dried with Na₂SO₄and concentrated under reduced pressure. Flash chromatography (ISCOsystem, silica (12 g), 0-5% methanol in dichloromethane) provided 5(3.21 mg, 71% yield).

Compound 6 was prepared according to General Method E using(R)-3-Boc-4-methyl-2, 2-dioxo-[1,2,3]oxathiazolidine in step 4.

General Method F.

Preparation of ethyl(5aR,8aS)-5,5a,6,7,8,8a-hexahydrocyclopenta[b]pyrazolo[1′,5′:1,2]pyrimido[4,5-e][1,4]oxazine-3-carboxylate (C-1)

Step 1. To a solution of C-1-1 (5.0 g, 28.1 mmol, 1 eq.) and C-1-2 (6.1g, 39.3 mmol, 1.4 eq.) in EtOH (56 mL) at 90° C. was added NaOEt (2.68M, 26.2 mL, 2.5 eq.) and was stirred for 6 hours. The reaction mixturecooled and diluted with Toluene (60 mL) and concentrated to drynessunder reduced pressure. The material was resuspended in Toluene (60 mL)and again concentrated to dryness and placed on a high vac overnight toprovide crude C-1-3. Crude material was used as is in next step.

Step 2. The crude C-1-3 from step 1 was suspended in POCl₃ (99 g, 60 mL,646 mmol, 23.00 eq.) and heated to 100° C. for 24 hours. The reactionwas cooled to room temperature and concentrated to dryness under reducedpressure. The crude material was suspended in DCM (100 mL) and water(100 mL) was added. The mixture was stirred for 30 min then extractedwith DCM (3×100 mL). The combined organic extracts were washed by brine(100 mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. Purification through a Silica plug (60 g Si),eluted with DCM (˜1.5 L) gave C-1-4 (5.68 g, 72% yield, purity=86% byLC/MS) as a yellow solid.

Step 3. To a solution of C-1-4 (5.68 g, 20.4 mmol) and NH₄Cl (5.46 g,102 mmol) in THF (68 mL), EtOH (204 mL) and water (136 mL) at 0° C. wasadded Zn powder (5.34 g, 81.7 mmol). The mixture was stirred at 0° C.for 3 hours. The reaction mixture was filtered through a celite pad andthe celite pad was rinsed with DCM (100 mL). The filtrate wasconcentrated to dryness under reduced pressure then resuspended in DCM(500 mL) dried with Na₂SO₄ and concentrated under reduced pressure.Purification using a silica plug (50 g Si) and elution with DCM providedC-1-5 (3.17 g, 63.8% yield) as a white solid.

Step 4. To a solution of C-1-5 (1.74 g, 7.1 mmol) and the HCl salt of(1S,2R)-2-aminocyclopentanol (1.08 g, 7.8 mmol) in EtOH (14 mL) wasadded DIEA (4.6 g, 6.2 mL 35.6 mmol). The mixture was heated to 80° C.for 1 hour. The reaction cooled and concentrated under reduced pressure.Flash chromatography (ISCO system, silica (40 g), 20-80% ethyl acetatein hexane) provided C-1-6 (2.13 g, 97% yield) as a white solid.

Step 5. To a solution of C-1-6 (1.0 g, 3.24 mmol) in DMSO (162 mL) wasadded Cs₂CO₃ (9.51 g, 29 mmol). The mixture was heated to 100° C. andstirred for 91 hours. The reaction mixture was cooled and quenched with30% brine solution (700 mL) then extracted with ethyl acetate (4×200mL). Combined extracts were washed with 15% brine solution (2×250 mL).Brine solutions were back extracted with ethyl acetate (1×250 mL).Organic extracts were combined and dried with brine (250 mL), Na₂SO₄ andconcentrated under reduced pressure to provide C-1 (803 mg, 86% yield,97% purity by LC/MS) as a light-yellow solid.

Compounds C-2, C-3, and C-4 were prepared according to General Method Fusing rac cis-2-aminocyclobutanol, (1S,2R)-2-aminocyclohexanol, and raccis-4-aminooxolan-3-ol, respectively in step 4.

MS [M + H] Compd# Structure m/z C-1

289.0 C-2

275.0 C-3

303.0 C-4

291.1

General Method G.

Preparation of tert-butyl{(2R)-1-[2-(chloromethyl)-4,6-difluorophenoxy]propan-2-yl}carbamate(D-1)

Step 1. To a solution of D-1-1 (200 mg, 1.27 mmol) and D-1-1A (315 mg,1.33 mmol) in DMF (6.3 mL) was added K₂CO₃ (437 mg, 3.2 mmol) Thereaction was stirred for 2 hours then quenched with citric acid solution(1 M in H₂O, 6 mL) was added and the mixture was vigorously stirred for30 minutes. The mixture was extracted with DCM (3×10 mL) and combinedorganic extracts were collected and dried over Na₂SO₄, filtered andconcentrated under reduced pressure and high vacuum to afforded desiredproduct D-1-2 (theoretical yield 399 mg). Compound was used as is.

Step 2. To a solution of D-1-2 (399 mg (theoretical), 1.27 mmol) in dryTHF (15 mL) was added LiBH₄ (193 mg, 8.86 mmol). The mixture was stirredfor 20 hours then quenched with water (25 mL) and stirred for 5 min. Themixture was extracted with DCM (3×15 mL), dried with Na₂SO₄ andconcentrated under reduced pressure. Flash chromatography (ISCO system,silica (24 g), 0-50% ethyl acetate in hexane) provided D-1-3 (33.2 mg,8% yield).

Step 3. To a solution of D-1-3 (33.2 mg, 105 μmol) and DIPEA (67.6 mg,91 μL, 523 μmol) in DCM (525 μL) at 0° C. was added MsCl (15 mg, 10 μL131 μmol) dropwise. The mixture stirred at 0° C. for 1 hour. Thereaction was quenched with water (3 mL) and 2M HCl (100 μL) thenextracted with DCM (3×5 mL). The organic phases were combined, driedover Na₂SO₄, and concentrated under reduced pressure. Flashchromatography (ISCO system, silica (12 g), 0-50% ethyl acetate inhexane) provided a mixture of D-1 and D-1A (40.2 mg, 91% yield).

General Method H.

Preparation of(S)-(2-((1-((tert-butoxycarbonyl)amino)propan-2-yl)oxy)-5-fluoropyridin-3-yl)methylmethanesulfonate (D-2)

Step 1. D-2-1 (7 g, 45.12 mmol) and pyridine hydrochloride (20.86 g,180.5 mmol) were mixed in a round bottom flask and heated up to 145° C.and the molten mixture was stirred at 145° C. for 30 min then cooleddown. The mixture was diluted with H₂O (200 mL) and ethyl acetate (200mL), partitioned and the aqueous layer was extracted with EA (5×100 mL),organic phases were combined and dried over Na₂SO₄, the solution wasthen concentrated under reduced pressure to afford desired product D-2-1(5.19 g, 36.78 mmol, 81.51% yield) as yellow solid.

Step 2. To an ice-bathed mixture of compound D-2-1 (2.37 mg, 16.79 mmol)and Cs₂CO₃ (21.88 g, 67.15 mmol in NMP (33.57 mL) was added compoundA-3-1A (4 g, 16.79 mmol), the reaction was stirred at 0° C. for 2 hours.The reaction was diluted with dichloromethane (200 mL) and H₂O (100 mL).Citric acid solution (1 M in H₂O, 100 mL) was added and the mixture wasvigorously stirred for 10 minutes, layers were separated, organic layerwas collected and dried over Na₂SO₄, filtered and concentrated underreduced pressure. Purification by flash chromatography (ISCO system,silica (80 g), 0-30% ethyl acetate in hexanes) afforded desired productD-2-2 (4.2 g, 14.06 mmol, 83.79% yield) as white solid.

Step 3. To an ice-bathed solution of compound D-2-2 (4.2 g, 14.06 mmol)in MeOH (46.88 mL) was added NaBH₄ (798.17 mg, 21.10 mmol). The reactionwas stirred under 0° C. for 1 hour. The reaction was quenched with H₂O(100 mL) and was extracted with dichloromethane (3×100 mL). The organicphases were combined and dried over Na₂SO₄, filtered and concentratedunder reduced pressure. Purification by flash chromatography (ISCOsystem, silica (80 g), 0-50% ethyl acetate in hexanes) afforded desiredproduct D-2-3 (3.46 g, 11.53 mmol, 81.96% yield) as colorless oil.

Step 4. To a solution of D-2-3 (2.41 g, 8.02 mmol) and the DIPEA (4.15g, 5.6 mL, 32.1 mmol) in DCM (14 mL) at 0° C. was added MsCl (1.10 g,0.74 mL 9.62 mmol) dropwise. The mixture stirred at 0° C. for 2 hours.The was quenched with 1% HCl solution (100 mL) and extracted with DCM(3×100 mL). The organic phases were combined, dried over Na₂SO₄, andconcentrated under reduced pressure. Flash chromatography (ISCO system,silica (80 g), 0-40% ethyl acetate in hexane) provided D-2 (2.0 g, 66%yield) as a white solid and D-2A (627 mg, 24% yield) as an oil.

Compound D-3 was prepared according to General Method H using(R)-3-boc-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine in step 2.

MS [M + Na] Compd# Structure m/z D-1

418.1 D-2

401.1 D-3

401.1

General Method I.

Preparation of(3aR,12R,20aS)-7,9-difluoro-12-methyl-2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-14(11H)-one(7)

Step 1. To a solution of C-1 (30 mg, 104 μmol) and D-1 (41 mg, 104 μmol)in DMF (1 mL) was added Cs₂CO₃ (102 mg, 312 μmol). The reaction wasstirred at room temperature for 4 hours. The reaction was cooled,diluted with DCM (3 mL), filtered through a syringe filter andconcentrated under reduced pressure. Flash chromatography (ISCO system,silica (12 g), 0-50% ethyl acetate in hexane) provided 7-1 (61 mg, 100%yield).

Step 2. Compound 7-1 was converted to 7 following the procedure used inGeneral Method E.

Compounds 8 and 9 were prepared according to General Method I usingstarting materials C-2 and D-2 in step 1 and separating thestereoisomers after the last step.

Compounds 10 and 11 were prepared according to General Method I usingstarting materials C-2 and D-3 in step 1 and separating thestereoisomers after the last step.

Compound 12 was prepared according to General Method I using startingmaterials C-3 and D-2 in step 1.

Compound 13 was prepared according to General Method I using startingmaterials C-3 and D-3 in step 1.

General Method J.

Preparation of(3aR,12R,20aS)-12-cyclopropyl-7-fluoro-2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-14(11H)-one(14)

Step 1. To a solution of 14-1 (1.0 g, 8.69 mmol) in dry MeOH (87 mL) wasadded HCl (4.0 M, 4.3 mL, 2.0 eq.) in dioxane. The mixture was heated to70° C. and stirred for 40 hours. The reaction mixture cooled andconcentrated to dryness under reduced pressure to provide crude 14-2.The material was used as is in next step.

Step 2. To a solution of crude 14-2 from step 1 in THF (60 mL) was addedBoc₂O (2.08 g, 9.54 mmol) and NaHCO₃ solution (1 M, 34.69 mL). Thereaction was stirred for 4 hours then diluted with water (50 mL) andthen extracted with ethyl acetate (3×50 mL). The combined organicextracts were washed by brine (50 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. Flashchromatography (ISCO system, silica (40 g), 0-50% ethyl acetate inhexane) provided 14-3 (1.66 g, 83% yield).

Step 3. To a solution of 14-3 (1.66 g, 7.24 mmol) in THF (36 mL) at 0°C. was added LiBH₄ (789 mg, 36 mmol). The mixture was slowly warmed toroom temperature and stirred for 20 hours. The reaction mixture wasquenched by addition of water (20 mL) and aqueous saturated NH₄Cl (25mL) then extracted with ethyl acetate (3×50 mL). Combined extracts weredried with brine (50 mL), Na₂SO₄ and concentrated under reducedpressure. Flash chromatography (ISCO system, silica (40 g), 10-40% ethylacetate in hexane) provide 14-4 (1.23 g, 84% yield).

Step 4. To a solution of Imidazole (1.0 g, 14.9 mmol) in DCM (16 mL) at−5° C. was added SOCl₂ (532 mg, 4.47 mmol, 324 μL) in DCM (5 mL)dropwise. The mixture was stirred at −5° C. for 1 hour. The mixture wascooled to −10° C. and 14-4 (0.5 g, 2.48 mmol) in DCM (4 mL) was addeddropwise. The mixture was slowly warmed to 10° C. and stirred at thistemperature for 2 hr. The reaction was quenched with water (10 mL) andstirred at 10° C. for 10 min. The organic layer was removed and washedwith 10% citric acid solution (10 mL) then dried with brine (5 mL) andNa₂SO₄ and concentrated under reduced pressure. Flash chromatography(ISCO system, silica (24 g), 0-20% ethyl acetate in hexane) provide 14-5(294 mg, 48% yield).

Step 5. To a solution of 14-5 (294 mg, 1.19 mmol) in DCM (5.66 mL) andNaIO4 (610.25 mg, 2.85 mmol) in H2O (5.66 mL) at 0° C. was addedRuCl₃*3H₂O (6.2 mg, 24 μmol). The reaction was warmed to roomtemperature and stirred for 1 hour. The reaction was quenched with water(15 mL) then extracted with DCM (3×15 mL). Combined extracts were driedwith brine (5 mL), Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (ISCO system, silica (12 g), 0-30% ethyl acetate inhexane) provide 14-6 (308 mg, 98% yield).

Step 6. To a solution of 5-3 (40 mg, 97 μmol) and 14-6 (32 mg, 121 μmol)in DMF (484 μL) was added CS2CO3 (95 mg, 290 μmol). The reaction mixturewas stirred for 1 hour then diluted with DCM (5 mL) and filtered throughsyringe filter then stirred with 20% citric acid solution (10 mL) for 30min. The mixture was extracted with DCM (3×15 mL) and combined extractsdried with Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (ISCO system, silica (12 g), 10-50% ethyl acetate inhexane) provide 14-7 (45.6 mg, 79% yield).

Step 7. Compound 14-7 was converted to 14 following the procedure usedin General Method E.

General Method K.

Preparation of(3aR,11S,21aS)-7-fluoro-11-methyl-2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20-(metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b][1,5,7,11]oxatriazacyclotetradecin-15-one(15)

Step 1. To a solution of 5-3 (50 mg, 121 μmol), 15-1-1A (27.5 mg, 145μmol) and PPh₃ (41 mg, 157 μmol) in DCM (194 μL) at 0° C. was added DIAD(41 mg, 157 μmol). The mixture was warmed to room temperature andstirred for 16 hours. The reaction cooled and diluted with DCM. Thesolution was filtered and the filtrate was concentrated under reducedpressure. Flash column chromatography (ISCO, silica, a 12 g, ethylacetate in hexanes) to afford 15-1 (58.8 mg, 83% yield)

Step 2. Compound 15-1 was converted to 15 following the procedure usedin General Method E.

Compounds 16 and 17 were prepared according to General Method K.

Compound 18 was prepared according to General Method J.

General Method L.

Preparation of(3aR,21aS)-7-fluoro-2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20-(metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b][1,5,7,11]oxatriazacyclotetradecin-15-one(19)

Step 1. To a solution of 5-3 (40 mg, 97 μmol) and 19-1-1A (23 mg, 116μmol) in DMF (300 uL) was added K₂CO₃ (27 mg, 194 μmol). The mixture wasmixture was stirred at room temperature for 16 hr. The reaction cooledand diluted with DCM (5 mL). The solution was filtered and the filtratewas concentrated under reduced pressure. The crude was purified by flashcolumn chromatography (ISCO, silica, 12 g, ethyl acetate in hexanes) toafford 15 (18.9 mg, 34% yield).

Step 2. Compound 19-1 was converted to 19 following the procedure usedin General Method E.

Compound 20 was prepared according to General Method K.

Compound 21 and 22 were prepared according to General Method J.

Compound 23 and 24 were prepared according to General Method K.

Compound 25 and 26 were prepared according to General Method J.

Compound 27, 28, and 29 were prepared according to General Method K.

Compound 30 and 31 were prepared according to General Method I usingstarting materials D-2A and C-4 in step 1 and separating thestereoisomers after the last step by flash column chromatography (ISCO,reverse phase C-18, 50 g, acetonitrile in water with 0.035% TFA).

General Method M.

Preparation of(3aR,12S,21aS)-7-fluoro-12-hydroxy-2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20-(metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b][1,5,7,11]oxatriazacyclotetradecin-15-one(32)

Step 1. To a solution of 32-1 (3.1 g, 34.03 mmol) and Boc anhydride(7.43 g, 34.03 mmol) in MeOH (68.05 mL) was added TEA (6.89 g, 68.05mmol, 9.48 mL). The mixture was stirred at room temperature for 16 hr.The reaction was concentrated under reduced pressure and purified byflash column chromatography (ISCO, silica, 40 g, methanol indichloromethane) to afford 32-2 (6.36 g, 33.26 mmol, 97.75% yield).

Step 2. 32-2 (6.36 g, 33.26 mmol) and imidazole (4.53 g, 66.52 mmol)were dissolved in THF (110.86 mL) and TBS chloride (6.02 g, 39.91 mmol)was added. The mixture was stirred for 2 hr then diluted with water (200mL) and extracted with DCM (3×200 mL). The combined organic phase waswashed with brine (200 mL) and dried over Na₂SO₄. The solution wasfiltered and the filtrate was concentrated under reduced pressure. Thecrude was purified by flash chromatography (ISCO system, silica, 80 g,0-40% ethyl acetate in hexanes) to afford 32-3 (8.75 g, 28.64 mmol,86.12% yield).

Step 3. To a solution of 32-3 (8.75 g, 28.64 mmol) and DIEA (11.11 g,85.93 mmol, 14.97 mL) in DCM (95.48 mL) at 0° C. was added MOM chloride(3.46 g, 42.96 mmol, 3.26 mL) slowly. The mixture was stirred for 16 hr.warming to ambient temperature. The reaction was quenched with water(100 mL) and extracted with DCM (3×100 mL). The combined extracts weredried over Na₂SO₄. The crude was purified by flash column chromatography(ISCO, silica, 80 g, 0-30% ethyl acetate in hexanes) to afford 32-4(7.44 g, 21.29 mmol, 74.31% yield).

Step 4. To a solution of 32-4 (7.44 g, 21.29 mmol) in THF (106.43 mL)was added TBAF Monohydrate (11.90 g, 42.57 mmol). The mixture wasstirred for 1 hr. then quenched with saturated aqueous NH₄Cl solution(10 mL) and diluted with DCM (100 mL). The mixture was dried over Na₂SO₄and filtered. The filtrate was concentrated under reduced pressure andthe crude was purified by flash column chromatography (ISCO, silica, 80g, ethyl acetate in hexanes) to afford 32-5 (4.67 g, 19.85 mmol, 93.25%yield).

Compound 32 was prepared following General Method J from 32-5 in step 4and 5-3 in step 6.

General Procedure N.

Preparation of(3aR,21aS)-7-fluoro-12,12-dihydroxy-2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20-(metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b][1,5,7,11]oxatriazacyclotetradecin-15-one(33)

To a solution of 32 (13.8 mg, 31.33 umol) in DCM (626.66 uL) was addedDess-Martin Periodinane (26.58 mg, 62.67 umol). The mixture was stirredat room temperature for 2 hr and quenched with saturated NaHCO₃ solution(5 mL). The mixture was extracted with DCM (3×5 mL) and the organiclayers dried over Na₂SO₄. The salts were filtered and the filtrateconcentrated under reduced pressure. The crude was purified by flashcolumn chromatography (ISCO, silica, 12 g, methanol in dichloromethane)and result mixture of products was stirred in acetonitrile (1 mL) withdrops of 2M HCl (2 drops), diluted with 2M sodium carbonate andextracted with dichloromethane (3×5 mL) to provide compound 33 (9.1 mg,19.94 μmol, 64% yield).

Compound 34 and 35 were prepared according to General Method K.

General Method O.

Preparation of(3aR,13R,21aS)-7-fluoro-13-methyl-2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20-(metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b][1,5,7,11]oxatriazacyclotetradecin-15-one(36) and(3aS,11S,20aR)-2-acetyl-7-fluoro-11-methyl-2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-(metheno)pyrazolo[4,3-f]pyrido[3,2-l]pyrrolo[3′,4′:5,6][1,4]oxazino[3,4-i][1,4,8,10]oxatriazacyclotridecin-14(11H)-one(37)

Step 1. To a solution of A-6 (255.4 mg, 748.15 umol, racemic mix)dissolved in anhydrous isopropanol (3.74 mL) at room temperature. DIEA(290.08 mg, 2.24 mmol, 390.94 uL) was added followed by C-1-5 (200.49mg, 822.96 umol). The mixture stirred at 80° C. for 18 hr and thenconcentrated under reduced pressure. The crude was purified by flashcolumn chromatography (ISCO, silica, 12 g, ethyl acetate in hexanes) toafford 36-1 (142.1 mg, 259.05 umol, 34.63% yield).

Step 2. To a solution of 36-1 (142.1 mg, 259.05 umol) in DMSO (1.30 mL)at room temperature, Cs₂CO₃ (168.81 mg, 518.10 umol) was added and themixture was stirred at room temperature for 72 hr. Diluted with water(15 mL) and extracted with DCM (5 mL×5). The organic layer was backwashed with water (10 mL) and brine (10 mL), then dried over sodiumsulfate. The mixture was filtered and the filtrate was concentratedunder reduced pressure. The crude was purified by flash columnchromatography (ISCO, silica, 12 g, ethyl acetate in hexanes) to afford36-2 (78.1 mg, 147.77 umol, 57.04% yield).

To a solution of 36-2 (20.5 mg, 38.79 umol) in anhydrous DCM (2 mL) wasadded HCl in dioxane (4 M, 1 mL). The mixture was stirred at ambienttemperature for 1 hr, concentrated under reduced pressure, and driedunder high vacuum to afford 36-3. Used directly in subsequent stepwithout further purification.

To crude 36-3 (14.5 mg, 33.85 umol) in DCM (338.46 uL) was added aceticacid (3.05 mg, 50.77 umol, 2.90 uL) and Hunig's base (21.87 mg, 169.23umol, 29.48 uL) followed by FDPP (16.91 mg, 44.00 umol) in one portion.Let stir for 72 hr then quenched with 2 M Na₂CO3 solution (5 mL).Mixture was stirred for 5 min then extracted with DCM (3×10 mL).Combined organic extracts were dried with Na₂SO₄ and concentrated underreduced pressure. Flash chromatography (ISCO system, silica 12 g,methanol in dichloromethane) provide 36-4 (9.9 mg, 21.04 umol, 62.18%yield)

To a solution of 36-4 (9.9 mg, 21.04 umol) dissolved in anhydrousethanol (1 mL) was added HCl in dioxane (4 M, 1 mL). The mixture wasstirred at 70° C. for 2 hr, then concentrated under reduced pressure anddried under high vacuum to afford 36-5. Used directly in subsequent stepwithout further purification.

36-5 was converted to compounds 36 and 37 as a racemic mixture (cis)following the procedure used in General Method E. The mixture wasseparated by flash column chromatography (ISCO, silica, 12 g, methanolin DCM) to provide 36 (1.23 mg, 2.63 umol, 26.89% yield) and 37 (1.38mg, 2.95 umol, 30.17% yield).

Compound 38, 39, 40, and 41 were prepared according to General Method K.

Compound 42 was prepared according to General Method K using ractrans-tert-butyl-3-hydroxycyclopentyl)carbamate and separating from 41after final step by flash column chromatography (ISCO, silica, 12 g,ethyl acetate in hexanes)

Compound 43 was prepared according to General Method M. Final productwas purified by flash column chromatography (ISCO, silica, 12 g, ethylacetate in hexanes)

General Method P.

Preparation of ethyl(5aS,8aR)-5,5a,6,7,8,8a-hexahydrocyclopenta[b]pyrazolo[1′,5′:1,2]pyrimido[4,5-e][1,4]oxazine-3-carboxylate(C-5)

Step 1: (1R, 2S)-2-aminocyclopentanol, HCl (3.6 g, 26.16 mmol) wasdissolved in anhydrous MeOH (96.89 mL) and treated with strongly basicion exchange resin (Amberlite IRN-78). 4-methoxybenzaldehyde (3.56 g,26.16 mmol) was added and the solution was stirred and heated to 65° C.for 3 hr. The mixture was cooled to room temperature and NaBH₄ (989.68mg, 26.16 mmol) was added. The reaction was stirred for 30 minutes, thenquenched with water (50 mL) and stirred for another 30 minutes. MeOH wasremoved under reduced pressure and the aqueous phase was extracted withDCM (3×50 mL). The organic phase was combined and dried over Na₂SO₄. Thecrude was purified by flash chromatography (ISCO system, 80 g, 0-10%MeOH/DCM) to give C-5-1 (4.92 g, 22.23 mmol, 84.98% yield)

Step 2: C-5-1 (2.6 g, 11.75 mmol), C-1-5 (2.5 g, 10.26 mmol) and DIEA(4.56 g, 35.25 mmol, 6.14 mL) were dissolved in i-PA (58.75 mL). Themixture was stirred at 80° C. for 16 hr after which volatiles wereremoved under reduced pressure. The resulting crude was purified byflash column chromatography (ISCO, silica, 80 g, 0-60% EtOAc in hexanes)to afford C-5-2 (2.1 g, 4.90 mmol, 41.72% yield).

Step 3: C-5-2 (2.1 g, 4.90 mmol) and Cs₂CO₃ (6.39 g, 19.61 mmol) weredissolved in DMSO (49.01 mL) and stirred at room temperature for 3 hr.Diluted with water (500 mL) and extracted with EtOAc (3×100 mL). Thecombined organic layer was washed with 20% brine solution (3×100 mL) anddried over Na₂SO₄. The crude was purified by flash chromatography (ISCO,80, 0-60% EtOAc in hexanes) to afford C-5-3 (1.69 g, 4.14 mmol, 84.42%yield).

C-5-3 (1.69 g, 4.14 mmol) was dissolved in TFA (41.38 mL) and stirred at75° C. for 16 hr, the reaction was cooled to room temperature and TFAwas removed under reduced pressure. The residue was treated with Sat.NaHCO₃ and EtOAc (100 mL each) and separated. The aqueous layer wasextracted again with EtOAc (2×50 mL) and the combined organic layer wasdried over Na₂SO₄. The crude was purified by flash column chromatography(ISCO, silica, 80 g, 0-80% EtOAc in Hexanes) to afford C-5 (1.12 g, 3.87mmol, 93.47% yield)

Compounds C-6 and C-7 were prepared according to General Method P using(1R, 2R)-2-aminocyclopentanol, HCl and (1S, 2S)-2-aminocyclopentanol,HCl respectively in step 1, and in high dilution (30 mM in DMSO) in step3.

MS [M + H] Compd# Structure m/z C-5

289.1 C-6

289.1 C-7

289.1

Compound 44 was prepared according to General Method I using startingmaterials C-5 and D-2.

Compounds 45, 46, 47, and 48 was prepared according to General Method K.

General Method Q

Preparation of(3aR,11S,20aS)-7-fluoro-11-(hydroxymethyl)-2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin-14(11H)-one(49)

Step 1. 49-1 (1.00 g, 13.50 mmol) was dissolved in THF (2.70 mL), water(2.70 mL) and methanol (21.60 mL). Ammonium chloride (1.66 g, 31.05mmol) was added followed by sodium azide (4.39 g, 67.50 mmol). Themixture was stirred at 75° C. for 3 hr and then cooled to ambienttemperature. Volume was carefully reduced under reduced pressure to athird and then diluted with DCM (50 mL) and water (50 mL). The layerswere partitioned and the aqueous layer was extracted 2× with DCM (2×20mL). The combined organic layer was washed with brine and dried oversodium sulfate. Flash column chromatography (ISCO, 24 g, silica, ethylacetate in hexanes) gave 49-2 (450.00 mg, 3.84 mmol, 28.46% yield)

Step 2. 49-2 (450.00 mg, 3.84 mmol) was dissolved in THF (19.20 mL) andPPh₃ (2.32 g, 8.83 mmol) was added. Stirred for 4 hr and water (1.59 g,88.32 mmol, 1.59 mL) was added and continued to stir for 16 hr when bocanhydride (1.09 g, 4.99 mmol) was added followed by sodium bicarbonate(32.26 mg, 384.00 umol). The mixture was stirred at RT for 4 hr andethyl acetate and water were added (30 mL each). The layers werepartitioned and the aqueous layer was extracted 2× with ethyl acetate(2×20 mL). The combined organic layer was washed with brine and thendried over sodium sulfate. Purified by flash column chromatography(ISCO, 24 g, silica, EtOAc in Hexanes) to provide 49-3 (525.30 mg, 2.75mmol, 71.54% yield).

Step 3. 49-3 (525.86 mg, 2.75 mmol) was dissolved in DCM (4.58 mL) andMOM-Cl (332.10 mg, 4.13 mmol, 313.30 uL) was added followed by DIEA(710.82 mg, 5.50 mmol, 960.57 uL) at 0° C. Stirred for 18 hr slowlywarming to RT. Water (5 mL) was added and the layers were partitioned.The aqueous layer was extracted 2× with DCM (5 mL). The combined organiclayer was washed with brine and dried over sodium sulfate. Salts werefiltered and volatiles were carefully removed via rotary evaporation attemperatures <30° C. to afford 49-4 (132.2 mg, 0.561 mmol, 20% yield).Used directly without further purification.

Compound 49 was prepared according to General Method K using 49-4 and5-3.

MS [M + H] Cpd Structure m/z ¹H NMR (DMSO-d₆) δ ppm  1

424.2 (500 MHz) 9.46 (dd, J = 5.73, 4.01 Hz, 1 H) 8.55 (s, 1 H) 7.98 (s,1 H) 7.36 (dd, J = 9.45, 3.15 Hz, 1 H) 7.07 − 7.13 (m, 1 H) 6.96 − 7.07(m, 1 H) 5.30 − 5.40 (m, 1 H) 4.63 − 4.74 (m, 1 H) 4.58 (ddd, J = 10.45,7.30, 2.86 Hz, 1 H) 4.53 (t, J = 4.01 Hz, 1 H) 4.21 (d, J = 14.89 Hz, 1H) 3.82 (ddd, J = 13.46, 6.01, 4.58 Hz, 1 H) 3.18 − 3.24 (m, 1 H) 2.32 −2.39 (m, 1 H) 2.10 − 2.20 (m, 1 H) 1.89 − 1.97 (m, 2 H) 1.69 − 1.79 (m,1 H) 1.50 − 1.60 (m, 1 H) 1.44 (d. J = 6.30 Hz, 3 H)  2

424.3 (300 MHz) 9.52 (br d, J = 5.78 Hz, 1 H) 8.63 (s, 1 H) 8.02 (s, 1H) 7.21 (dd, J = 8.99 ,2.29 Hz, 1 H) 6.97 − 7.13 (m, 2 H) 5.46 (d, J =15.04 Hz, 1 H) 4.45 − 4.59 (m, 1 H) 4.07 − 4.27 (m, 3 H) 3.86 − 3.99 (m,1 H) 3.06 − 3.19 (m, 1 H) 1.63 − 2.22 (m, 5 H) 1.44 (d, J = 6.05 Hz, 3H)  3

442.2 (500 MHz) 9.43 (t, J = 5.2 Hz, 1H), 8.58 (s, 1H), 7.99 (s, 1H),7.25 − 7.11 (m, 2H), 5.30 (d, J = 14.8 Hz, 1H), 5.04 − 5.00 (m, 1H),4.64 (t, J = 3.8 Hz, 1H), 4.48 (ddd, J = 2.9, 7.3, 10.6 Hz, 1H), 4.26(d, J = 15.1 Hz, 1H), 3.53 − 3.47 (m, 2H), 2.34 − 2.29 (m, 1H), 2.18 −2.10 (m, 1H), 1.98 − 1.91 (m, 2H), 1.73 (brdd, J = 8.8, 17.8 Hz, 1H),1.60 − 1.54 (m, 1H), 1.46 (d, J = 6.0 Hz, 3H)  4

426.2 (500 MHz) 9.40 (br t, J = 4.58 Hz, 1 H) 8.66 (s, 1 H) 8.02 (s, 1H) 7.43 (dd, J = 9.45, 2.58 Hz, 1 H) 7.06 − 7.15 (m, 1 H) 6.98 − 7.06(m, 1 H) 5.36 (d, J = 14.89 Hz, 1H) 4.96 − 5.07 (m, 1 H) 4.85 (br s, 1H)4.62 − 4.75 (m, 1 H) 4.33 (t, J = 7.45 Hz, 1 H) 4.16 − 4.29 (m, 2 H)4.03 (d, J = 10.88 Hz, 1 H) 3.77 − 3.86 (m, 1 H) 3.57 (t, J = 8.88 Hz, 1H) 3.19 − 3.24 (m, 1 H) 1.44 (d, J = 5.73 Hz, 3H)  5

425.3 (300 MHz) 9.36 − 9.45 (m, 1 H) 8.55 (s, 1 H) 8.07 (d, J = 2.93 Hz,1 H) 7.93 − 8.02 (m, 2 H) 5.10 − 5.27 (m, 2 H) 4.60 (ddd, J = 10.45,7.34, 3.30 Hz, 1 H) 4.48 − 4.54 (m, 1 H) 4.33 (d, J = 14.95 Hz, 1 H)3.93 (ddd, J = 12.95, 8.05, 4.49 Hz, 1 H) 3.09 − 3.21 (m, 1 H) 2.29−2.40 (m, 1 H) 2.06 − 2.17 (m, 1H) 1.86-2.00 (m, 2 H) 1.66 − 1.80 (m, 1H) 1.49 −1.63 (m, 1 H) 1.45 (d, J = 6.14 Hz, 3 H)  6

425.1 (500 MHz) 9.53 (d, J = 8.02 Hz, 1 H) 8.55 (s, 1 H) 8.09 (d, J =2.86 Hz, 1 H) 8.03 (dd, J = 8.59, 2.86 Hz, 1 H) 7.99 (s, 1 H) 5.32 (d, J= 14.89 Hz, 1 H) 4.70 (dd, J = 10.88, 4.01 Hz, 1 H) 4.61 (ddd, J =10.45, 7.30, 3.44 Hz, 1 H) 4.48 (t, J = 4.01 Hz, 1 H) 4.35 (d, J = 14.89Hz, 1H) 4.26 (br dd, J = 11.17, 6.59 Hz, 1 H) 4.14 (dd, J = 10.60, 1.43Hz, 1 H) 2.33 − 2.43 (m, 1 H) 2.07 − 2.19 (m, 1 H) 1.88 − 1.98 (m, 2 H)1.69 − 1.82 (m, 1 H) 1.50 − 1.62 (m, 1 H) 1.36 (d, J = 6.87 Hz, 3 H)  7

442.1 (500 MHz) 9.89 (br d, J = 8.59 Hz, 1 H) 8.58 (s, 1 H) 8.01 (s, 1H) 7.19 − 7.30 (m, 2 H) 5.46 (br d, J = 14.89 Hz, 1 H) 4.74 (br dd, J =9.45, 6.01 Hz, 1 H) 4.53 − 4.64 (m, 2 H) 4.25 (br d, J = 15.47 Hz, 1 H)4.20 (br t, J = 7.16 Hz, 1 H) 3.93 − 4.05 (m, 1 H) 2.31 − 2.40 (m, 1 H)2.09 − 2.20 (m, 1 H) 1.87 − 1.97 (m, 2 H) 1.68 − 1.79 (m, 1 H) 1.48 −1.59 (m, 1 H) 1.33 (d, J = 6.87 Hz, 3 H)  8

411.1 9.37 (br d, J = 6.30 Hz, 1 H) 8.62 (s, 1 H) 8.06 (d, J = 2.86 Hz,1 H) 8.01 (s, 1 H) 7.90 (dd, J = 8.88, 2.58 Hz, 1H) 5.26 (d, J = 15.47Hz, 1 H) 5.11 − 5.20 (m, 1 H) 5.05 (q, J = 6.87 Hz, 1 H) 4.91 (br d, J =2.86 Hz, 1 H) 4.14 (d, J = 14.89 Hz, 1 H) 3.93 − 4.02 (m, 1 H) 3.07 −3.19 (m, 1 H) 2.28 − 2.35 (m, 1 H) 2.11 − 2.22 (m, 1 H) 2.02 − 2.09 (m,1 H) 1.94 − 2.02 (m, 1 H) 1.46 (d, J = 6.30 Hz, 3 H)  9

411.0 9.38 (br d, J = 5.73 Hz, 1 H) 8.68 (s, 1 H) 8.08 (d, J = 2.86 Hz,1 H) 8.03 (s, 1 H) 7.42 (dd, J = 8.59, 2.86 Hz, 1H) 5.34 (br d, J =14.89 Hz, 1 H) 5.10 − 5.21 (m, 1 H) 4.74 (br d, J = 2.29 Hz, 1 H) 4.37 −4.48 (m, 1 H) 4.24 (d, J = 14.89 Hz, 1 H) 3.96 (ddd, J = 13.03, 8.16,4.58 Hz, 1 H) 3.11 − 3.20 (m, 1 H) 2.60 − 2.72 (m, 1 H) 2.41 − 2.48 (m,1 H) 2.19 − 2.31 (m, 1 H) 2.00 − 2.08 (m, 1 H) 1.46 (d, J = 6.30 Hz, 3H) 10

411.0 (500 MHz) 9.43 (d, J = 8.02 Hz, 1 H) 8.62 (s, 1 H) 8.07 (d, J =2.86 Hz, 1 H) 8.01 (s, 1 H) 7.93 (dd, J = 8.59, 2.86 Hz, 1 H) 5.34 (dd,J = 14.89, 1.15 Hz, 1 H) 5.03 (q, J = 6.68 Hz, 1 H) 4.90 (dt, J = 5.73,2.86 Hz, 1 H) 4.75 (dd, J = 10.60, 4.30 Hz, 1 H) 4.25 − 4.34 (m, 1 H)4.16 (d, J = 10.88 Hz, 1 H) 4.13 (dd, J = 9.17, 1.72 Hz, 1 H) 2.27 −2.35 (m, 1 H) 2.13 − 2.22 (m, 1 H) 2.05 − 2.13 (m, 1 H) 1.98 − 2.05 (m,1 H) 1.38 (d. J = 6.87 Hz, 3 H) 11

411.0 (500 MHz) 9.47 (d, J = 8.02 Hz, 1 H) 8.68 (s, 1 H) 8.10 (d, J =3.44 Hz, 1 H) 8.03 (s, 1 H) 7.49 (dd, J = 8.59, 2.86 Hz, 1 H) 5.45 (d, J= 16.04 Hz, 1 H) 4.73 (br d, J = 4.01 Hz, 1 H) 4.70 (dd, J = 10.88, 4.01Hz, 1 H) 4.42 − 4.48 (m, 1 H) 4.24 − 4.31 (m, 2 H) 4.15 (dd, J = 10.60,2.00 Hz, 1 H) 2.65 − 2.73 (m, 1 H) 2.42 (dt, J = 18.62, 9.59 Hz, 1 H)2.19 − 2.28 (m, 1 H) 1.98 − 2.04 (m, 1 H) 1.37 (d, J = 6.30 Hz, 3 H) 12

439.1 (500 MHz) 9.41 (br d, J = 7.45 Hz, 1 H) 8.55 (s, 1 H) 8.06 (br s,1 H) 7.97 (d, J = 1.72 Hz, 1 H) 7.95 (br d, J = 9.17 Hz, 1 H) 5.07 −5.20 (m, 2 H) 4.50 (br s, 1 H) 4.33 (br d, J = 14.89 Hz, 1 H) 4.26 (brs, 1 H) 3.87 − 3.99 (m, 1 H) 3.09 − 3.19 (m, 1 H) 2.06 − 2.17 (m, 2 H)1.87 (br t, J = 12.32 Hz, 1 H) 1.78 (br d, J = 1.15 Hz, 1 H) 1.47 − 1.60(m, 2H) 1.45 (br d, J = 5.73 Hz, 3 H) 1.41 (br d, J = 8.59 Hz, 2H) 13

439.1 (500 MHz) 9.51 (d, J = 8.59 Hz, 1 H) 8.54 (s, 1 H) 8.08 (d, J =3.44 Hz, 1 H) 8.00 (dd, J = 9.16, 2.86 Hz, 1 H) 7.97 (s, 1 H) 5.21 (dd,J = 14.89,1.15 Hz, 1 H) 4.70 (dd, J = 10.60, 4.30 Hz, 1 H) 4.47 (br s, 1H) 4.35 (d, J = 14.89 Hz, 1 H) 4.21 − 4.31 (m, 2 H) 4.14 (dd, J = 10.31,1.72 Hz, 1 H) 2.07 − 2.19 (m, 2H) 1.83 −1.92 (m, 1 H) 1.78 (br s, 1 H)1.38 − 1.59 (m, 4 H) 1.36 (d, J = 6.30 Hz, 3 H) 14

451.1 (500 MHz) 9.73 (d, J = 9.16 Hz, 1 H) 8.55 (s, 1 H) 8.10 (d, J =2.86 Hz, 1 H) 8.05 (dd, J = 8.59, 2.86 Hz, 1 H) 7.99 (s, 1 H) 5.30 −5.38 (m, 1 H) 4.64 − 4.69 (m, 1 H) 4.58 − 4.64 (m, 1 H) 4.47 (t, J =3.72 Hz. 1 H) 4.37 (d, J = 8.02 Hz, 1 H) 4.34 (d, J = 4.01 Hz, 1 H) 3.75(td, J = 8.59, 4.01 Hz, 1 H) 2.33 − 2.44 (m, 1 H) 2.07 − 2.19 (m, 1 H)1.86 − 1.99 (m, 2 H) 1.67 − 1.81 (m, 1 H) 1.51 − 1.63 (m, 1 H) 1.20 −1.33 (m, 1 H) 0.42 − 0.55 (m, 3 H) 0.27 − 0.37 (m, 1 H) 15

439.1 (500 MHz) 8.52 (s, 1 H) 8.11 (t, J = 4.30 Hz, 1 H) 8.04 (d, J =2.86 Hz, 1 H) 7.99 (s, 1 H) 7.86 (dd, J = 8.59, 2.86 Hz, 1 H) 5.55 (brt, J = 6.59 Hz, 1 H) 5.28 (dd, J = 14.89, 1.15 Hz, 1 H) 4.54 − 4.58 (m,1 H) 4.50 − 4.54 (m, 1 H) 4.29 (d, J = 14.89 Hz, 1 H) 3.61 − 3.68 (m, 1H) 3.34 − 3.37 (m, 1 H) 2.32 − 2.38 (m, 1 H) 2.09 − 2.16 (m, 2 H) 1.88 −1.97 (m, 3 H) 1.69 − 1.76 (m, 1 H) 1.51 − 1.59 (m, 1 H) 1.30 (d, J =6.30 Hz, 3 H) 16

439.1 (500 MHz) 8.55 (s, 1 H) 8.48 (s, 1 H) 8.14 (d, J = 6.87 Hz, 1 H)8.05 − 8.09 (m, 2 H) 7.92 (dd, J = 8.59, 2.86 Hz, 1 H) 7.44 (dd, J =8.59, 2.86 Hz, 1 H) 5.54 (t, J = 12.03 Hz, 1 H) 5.30 − 5.42 (m, 2 H)4.76 − 4.83 (m, 1 H) 4.47 − 4.56 (m, 2 H) 4.17 − 4.38 (m, 5 H) 4.05(ddd, J = 10.60, 6.87, 3.72 Hz, 1 H) 3.91 − 3.97 (m, 1 H) 2.50 − 2.56(m, 1 H) 2.06 − 2.38 (m, 5 H) 1.82 − 2.00 (m, 6 H) 1.62 − 1.75 (m, 2 H)1.18 (d, J = 6.30 Hz, 3 H) 17

439.1 (500 MHz) 8.60 (s, 1 H) 8.53 (s, 1 H) 8.17 − 8.22 (m, 1 H) 8.06(d, J = 2.86 Hz, 1 H) 8.02 (s, 1 H) 7.99 (s, 1 H) 7.87 (dd, J = 8.88,2.58 Hz, 1 H) 7.56 (dd, J = 8.59, 3.44 Hz, 1 H) 5.27 (dd, J = 14.89,1.15 Hz, 1 H) 4.92 − 4.96 (m, 1 H) 4.51 − 4.57 (m, 2 H) 4.31 (d, J =15.47 Hz, 1 H) 3.95 (dd, J = 11.17, 8.88 Hz, 1 H) 3.88 (br dd, J =13.17, 8.02 Hz, 1 H) 3.06 (ddd, J = 13.75, 8.59, 2.86 Hz, 1 H) 2.30 −2.38 (m, 2 H) 2.09 − 2.16 (m, 1 H) 1.90 − 1.98 (m, 2 H) 1.69 − 1.77 (m,1 H) 1.52 − 1.60 (m. 1 H) 1.03 (d, J = 6.87 Hz, 3 H) 18

437.1 (500 MHz) 9.02 − 9.15 (m, 1 H) 8.47 − 8.63 (m, 1 H) 8.07 (d, J =2.86 Hz, 1 H) 8.02 (dd, J = 8.88, 2.58 Hz, 1 H) 7.90 − 7.96 (m, 1 H)5.34 − 5.56 (m, 1 H) 4.79 − 4.91 (m, 1 H) 4.60 (ddd, J = 10.74, 7.30,3.15 Hz, 1 H) 4.46 (t, J = 3.72 Hz, 1 H) 4.26 − 4.36 (m, 1 H) 3.71 −3.85 (m, 1 H) 2.32 − 2.41 (m, 1 H) 2.06 − 2.20 (m, 1 H) 1.87 − 2.03 (m,3 H) 1.67 − 1.82 (m, 1 H) 1.51 − 1.63 (m, 1 H) 0.99 − 1.11 (m, 1 H) 0.90− 0.98 (m, 1 H) 0.73 − 0.87 (m, 1 H) 19

425.1 (500 MHz) 8.60 (s, 1 H) 8.53 (s, 1 H) 8.09 − 8.14 (m, 1 H) 8.06(d, J = 2.86 Hz, 1 H) 8.00 (s, 1 H) 7.89 (dd, J = 9.17, 2.86 Hz, 1 H)7.50 (dd, J = 8.59, 2.29 Hz, 1 H) 5.32 (dd, J = 14.89, 1.15 Hz, 1 H)4.95 − 5.05 (m, 1 H) 4.51 − 4.59 (m, 2 H) 4.27 − 4.33 (m, 1 H) 4.17 −4.24 (m, 1 H) 3.67 − 3.74 (m, 1 H) 3.35 − 3.41 (m, 1 H) 2.30 − 2.40 (m,1 H) 2.10 − 2.18 (m, 2 H) 1.86 − 2.04 (m, 5 H) 1.65 − 1.79 (m, 1 H)1.48-1.61 (m, 1 H) 20

451.1 (500 MHz) 8.87 (t, J = 5.16 Hz, 1 H) 8.63 (s, 1 H) 8.05 (d, J =2.86 Hz, 1 H) 8.01 (s, 1 H) 7.61 (dd, J = 8.88, 2.58 Hz, 1 H) 5.30 −5.38 (m, 1 H) 4.93 (dd, J = 15.18, 1.43 Hz, 1 H) 4.53 (d, J = 15.47 Hz,1 H) 4.20 − 4.33 (m, 2 H) 3.81 (dt, J = 13.17, 4.87 Hz, 1 H) 3.22 − 3.31(m, 1 H) 1.61 (s, 3 H) 1.45 (d, J = 6.30 Hz, 3 H) 1.36 (s, 3 H) 21

439.1 (500 MHz) 9.09 (s, 1 H) 8.51 − 8.63 (m, 1 H) 8.06 − 8.14 (m, 2 H)7.94 − 7.99 (m, 1 H) 5.31 − 5.59 (m, 1 H) 4.56 − 4.71 (m, 2 H) 4.47 (t,J = 3.81 Hz, 1 H) 4.32 (br d, J = 14.67 Hz, 1 H) 3.90 − 3.98 (m, 1 H)2.36 − 2.44 (m, 1 H) 2.08 − 2.18 (m, 1 H) 1.89 − 1.98 (m, 2 H) 1.70 −1.82 (m, 1 H) 1.62 (s, 3 H) 1.53 − 1.59 (m, 1 H) 1.49 (s, 3 H) 22

451.2 (500 MHz) 8.94 − 9.12 (m, 1 H) 8.49 − 8.65 (m, 1 H) 8.11 (d, J =2.86 Hz, 1 H) 8.06 (dd, J = 8.59, 2.29 Hz, 1 H) 7.94 − 8.02 (m, 1 H)5.21 − 5.48 (m, 1 H) 4.74 − 4.95 (m, 1 H) 4.54 − 4.64 (m, 1 H) 4.46 (t,J = 3.44 Hz, 1 H) 4.32 − 4.40 (m, 1 H) 4.23 − 4.32 (m, 1 H) 3.38 − 3.60(m, 1 H) 2.65 − 2.84 (m, 1 H) 2.34 − 2.44 (m, 1 H) 2.16 − 2.26 (m, 1 H)2.02 − 2.16 (m, 2 H) 1.77 − 1.99 (m, 4 H) 1.66 − 1.77 (m, 1 H) 1.48 −1.62(m, 1 H) 23

465.2 (500 MHz) 8.47 − 8.64 (m, 1 H) 8.04 − 8.13 (m, 2 H) 7.99 − 8.04(m, 1 H) 7.51 − 7.97 (m, 1 H) 5.26 − 5.46 (m, 1 H) 5.06 − 5.25 (m, 1 H)4.53 − 4.60 (m, 1 H) 4.51 (t, J = 3.72 Hz, 1 H) 4.23 − 4.34 (m, 1 H)4.04 − 4.14 (m, 1 H) 3.68 − 3.79 (m, 1 H) 2.31 − 2.41 (m, 1 H) 2.10 −2.22 (m, 2 H) 1.87 − 2.04 (m, 7 H) 1.77 − 1.85 (m, 1 H) 1.66 − 1.75 (m,1H) 1.49-1.61 (m, 1 H) 24

451.2 (500 MHz) 9.31 (d, J = 6.87 Hz, 1 H) 8.54 (s, 1 H) 8.04 (d, J =2.86 Hz, 1 H) 7.97 (s, 1 H) 7.95 (dd, J = 8.88, 2.58 Hz, 1 H) 5.73 (td,J = 6.30, 3.44 Hz, 1 H) 5.22 (d, J = 14.89 Hz, 1 H) 4.57 (ddd, J =10.45, 7.30, 3.44 Hz, 1 H) 4.51 (t, J = 4.01 Hz, 1 H) 4.34 (d, J = 14.89Hz, 1 H) 4.25 (quin, J = 7.02 Hz, 1 H) 2.31 − 2.40 (m, 1 H) 2.03 − 2.21(m, 3 H) 1.89 − 1.98 (m, 2 H) 1.78 − 1.89 (m, 2 H) 1.67 − 1.78 (m, 2 H)1.51 − 1.65 (m, 2H) 25

487.1 (500 MHz) 8.94 − 9.15 (m, 1 H) 8.52 − 8.67 (m, 1 H) 8.12 (d, J =2.29 Hz, 1 H) 8.02 − 8.09 (m, 1 H) 7.93 − 8.02 (m, 1 H) 5.20 − 5.43 (m,1 H) 4.99 − 5.12 (m, 1 H) 4.59 (ddd, J = 10.45, 7.59, 3.15 Hz, 1 H) 4.47(t, J = 3.72 Hz, 1 H) 4.25 − 4.36 (m, 2 H) 3.89 − 4.19 (m, 1 H) 3.57 −3.85 (m, 1 H) 2.99 − 3.21 (m, 1 H) 2.74 − 2.87 (m, 1 H) 2.34 − 2.44 (m,1 H) 2.06 − 2.21 (m, 1 H) 1.88 − 1.99 (m, 2 H) 1.69 − 1.82 (m, 1 H)1.48-1.61 (m, 1H) 26

465.2 (500 MHz) 9.19 (s, 1 H) 8.47 − 8.64 (m, 1 H) 8.04 − 8.18 (m, 2 H)7.92 − 8.01 (m, 1 H) 5.26 − 5.59 (m, 1 H) 4.52 − 4.71 (m, 2 H) 4.46 (t,J = 4.01 Hz, 1 H) 4.23 − 4.36 (m, 1 H) 3.95 − 4.07 (m, 1 H) 2.87 (ddd, J= 13.32, 9.02, 4.01 Hz, 1 H) 2.31 − 2.45 (m, 1 H) 2.06 − 2.17 (m, 1 H)1.85 − 2.06 (m, 5 H) 1.63 − 1.85 (m, 3 H) 1.50 − 1.63 (m, 2 H) 1.39−1.50 (m, 1 H) 27

419.2 (500 MHz) 8.49 − 8.62 (m, 1 H) 8.12 − 8.26 (m, 1 H) 7.92 − 8.09(m, 3 H) 5.31 − 5.51 (m, 1 H) 5.00 − 5.18 (m, 1 H) 4.57 (ddd, J = 10.60,7.45, 3.15 Hz, 1 H) 4.50 − 4.53 (m, 1 H) 4.29 − 4.34 (m, 1 H) 3.65 −3.72 (m, 1 H) 3.42 − 3.49 (m, 1H) 3.13 (dd, J = 13.75, 2.29 Hz, 1H) 2.32− 2.40 (m, 1 H) 2.08 − 2.19 (m, 1 H) 1.88 − 1.99 (m, 2 H) 1.68 − 1.78(m, 1 H) 1.51 −1.63 (m, 1 H) 1.21 (s, 3H) 1.02 (s, 3H) 28

439.1 (500 MHz) 8.49 − 8.61 (m, 1 H) 7.98 − 8.19 (m, 3 H) 7.45 − 7.97(m, 1 H) 4.75 − 5.66 (m, 2 H) 4.49 − 4.61 (m, 1 H) 4.18 − 4.43 (m, 3 H)3.92 − 4.14 (m, 1 H) 2.53 − 2.66 (m, 1 H) 2.09 − 2.40 (m, 2 H) 1.46 −2.01 (m, 5 H) 1.23 (dd, J = 18.33, 6.87 Hz, 3 H) 29

414.3 (500 MHz) 8.50 − 8.64 (m, 1 H) 8.18 − 8.28 (m, 1 H) 7.99 − 8.09(m, 2 H) 7.83 − 7.98 (m, 1 H) 5.23 − 5.42 (m, 1 H) 4.78 −4.99 (m, 1 H)4.49 − 4.61 (m, 2 H) 4.26 − 4.34 (m, 1 H) 3.92 − 4.00 (m, 1 H) 3.57 −3.91 (m, 1 H) 2.97 − 3.12 (m, 1 H) 2.29 − 2.39 (m, 2 H) 2.07-2.18 (m, 1H) 1.87-2.00 (m, 2 H) 1.66 − 1.79 (m, 1 H) 1.49 − 1.61 (m, 1 H) 1.03(dd, J = 6.87, 2.86 Hz, 3 H) 30

427.1 (500 MHz) 9.33 − 9.37 (m, 1 H) 8.67 (s, 1 H) 8.08 (d, J = 2.86 Hz,1 H) 8.02 − 8.06 (m, 2 H) 5.23 (d, J = 15.47 Hz, 1 H) 5.14 − 5.20 (m, 1H) 5.01 − 5.07 (m, 1 H) 4.82 (t, J = 3.44 Hz, 1 H) 4.30 − 4.40 (m, 2 H)4.19 (dd, J = 10.31, 3.44 Hz, 1 H) 4.03 (d, J = 10.88 Hz, 1 H) 3.90 −3.97 (m, 1 H) 3.53 − 3.59 (m, 1 H) 3.15 (ddd, J = 13.60, 8.74, 2.86 Hz,1 H) 1.45 (d, J = 5.73 Hz, 3 H) 31

427.1 (500 MHz) 9.24 (dd, J = 6.59, 3.15 Hz, 1 H) 8.75 (s, 1 H) 8.04 −8.09 (m, 2 H) 7.39 (dd, J = 8.59, 2.86 Hz, 1 H) 5.37 (d, J = 14.89 Hz, 1H) 5.21 − 5.28 (m, 1 H) 4.65 (t, J = 3.72 Hz, 1 H) 4.61 (t, J = 7.16 Hz,1 H) 4.46 − 4.51 (m, 1 H) 4.35 (d, J = 14.89 Hz, 1 H) 4.29 (dd, J =10.88, 4.58 Hz, 1 H) 4.03 (d, J = 10.31 Hz, 1 H) 3.88 − 3.95 (m, 1 H)3.80 − 3.85 (m, 1 H) 3.17 − 3.24 (m, 1 H) 1.46 (d, J = 6.30 Hz, 3 H) 32

441.0 (500 MHz) 8.53 (s, 1 H) 8.13 (dd, J = 8.59, 1.72 Hz, 1 H) 8.05 (d,J = 2.86 Hz, 1 H) 7.99 (s, 1 H) 7.85 (dd, J = 8.59, 2.86 Hz, 1 H) 5.37(d, J = 4.58 Hz, 1 H) 5.28 (dd, J = 15.18, 1.43 Hz, 1 H) 5.01 (br d, J =9.74 Hz, 1 H) 4.49 − 4.58 (m, 2 H) 4.30 (d, J = 15.47 Hz, 1 H) 4.00 −4.10 (m, 2 H) 3.91 − 3.98 (m, 1 H) 3.12 (ddd, J = 13.17, 8.59, 2.29 Hz,1 H) 2.29 − 2.38 (m, 1 H) 2.07 − 2.19 (m, 1 H) 1.86− 1.98 (m, 2 H) 1.66− 1.76 (m, 1H) 1.48 − 1.59 (m, 1 H) 33

457.0 34

453.2 (500 MHz) 8.45 − 8.58 (m, 1 H) 8.08 (d, J = 2.86 Hz, 1 H) 7.96 −8.02 (m, 2 H) 7.81 − 7.89 (m, 1 H) 5.39 − 5.57 (m, 1 H) 4.89 − 5.15 (m,1 H) 4.54 − 4.60 (m, 1 H) 4.44 (t, J = 3.72 Hz, 1 H) 4.24 (d, J = 15.47Hz, 1 H) 4.06 (br dd, J = 11.17, 5.44 Hz, 1 H) 1.66 − 2.44 (m, 8 H),1.54 − 1.58 (m, 3 H) 1.50 − 1.53 (m, 3 H) 35

439.2 (500 MHz) 8.59 (s, 1 H) 8.52 (s, 1 H) 8.09 (br t, J = 4.58 Hz, 1H) 8.03 (d, J = 2.86 Hz, 1 H) 8.00 (s, 1 H) 7.44 (dd, J = 8.59, 2.86 Hz,1 H) 5.62 (br t, J = 6.30 Hz, 1 H) 5.40 (dd, J = 15.18, 1.43 Hz, 1 H)4.23 − 4.31 (m, 2 H) 4.06 (ddd, J = 10.60, 6.87, 3.72 Hz, 1 H) 3.56 −3.65 (m, 1 H) 2.52 − 2.57 (m, 1 H) 2.14 − 2.27 (m, 2 H) 1.86 − 2.01 (m,5 H) 1.66 − 1.74 (m, 1 H) 1.29 − 1.33 (m, 4 H) 36

468.2 (500 MHz) 9.38 (br d, J = 4.01 Hz, 1 H) 8.68 (d, J = 9.74 Hz, 1 H)8.09 (t, J = 2.58 Hz, 1 H) 7.97 − 8.05 (m, 2 H) 4.98 − 5.27 (m, 3 H)4.78 − 4.88 (m, 1 H) 4.22 − 4.44 (m, 2 H) 3.80 − 3.99 (m, 2 H) 3.67 −3.69 (m, 1 H) 3.03 − 3.19 (m, 2 H) 2.00 (d, J = 7.45 Hz, 3 H) 1.46 (d, J= 6.30 Hz, 3 H) 37

468.2 (500 MHz) 9.17 − 9.24 (m, 1 H) 8.75 (d, J = 13.75 Hz, 1 H) 8.10(t, J = 3.15 Hz, 1 H) 8.05 − 8.08 (m, 1 H) 7.39 − 7.57 (m, 1H) 5.35 −5.44 (m, 1 H) 5.21 − 5.30 (m, 1 H) 4.28 − 4.73 (m, 4 H) 3.62 − 4.02 (m,4 H) 3.19 − 3.24 (m, 1 H) 2.01 − 2.10 (m, 3 H) 1.46 (d, J = 6.30 Hz, 3H) 38

443.2 (500 MHz) 8.54 (s, 1 H) 8.19 (t, J = 4.87 Hz, 1 H) 8.09 (d, J =2.86 Hz, 1 H) 8.01 (s, 1 H) 7.94 (dd, J = 8.88, 2.58 Hz, 1 H) 5.30 −5.41 (m, 1 H) 5.27 (dd, J = 14.89, 1.15 Hz, 1 H) 5.07 − 5.21 (m, 1 H)4.50 − 4.58 (m, 2 H) 4.30 − 4.39 (m, 2 H) 3.93 − 4.02 (m, 1 H) 3.56 −3.69 (m, 1 H) 2.30 − 2.39 (m, 1 H) 2.09 − 2.18 (m, 1 H) 1.89 − 1.99 (m,2 H) 1.65 − 1.79 (m, 1 H) 1.50 − 1.65 (m. 1 H) 39

443.2 (500 MHz) 8.53 − 8.62 (m, 1 H) 8.10 − 8.27 (m, 1 H) 8.08 (t, J =2.58 Hz, 1 H) 8.02 (d, J = 2.29 Hz, 1 H) 7.49 − 7.97 (m, 1H) 5.44 − 5.53(m, 1 H) 5.33 − 5.43 (m, 1 H) 5.00 − 5.21 (m, 1 H) 4.52 − 4.60 (m, 1 H)4.22 − 4.41 (m, 3 H) 3.95 − 4.14 (m, 1 H) 3.52 − 3.67 (m, 1 H) 2.32 −2.40 (m, 1 H) 2.09 − 2.27 (m, 1 H) 1.87 − 2.00 (m, 2 H) 1.66 − 1.78 (m,1 H) 1.46 − 1.58 (m, 1 H) 40

461.1 (500 MHz) 8.53 − 8.62 (m, 1 H) 8.10 − 8.27 (m, 1 H) 8.08 (t, J =2.58 Hz, 1 H) 8.02 (d, J = 2.29 Hz, 1 H) 7.49 − 7.97 (m, 1H) 5.44 − 5.53(m, 1 H) 5.33 − 5.43 (m, 1 H) 5.00 − 5.21 (m, 1 H) 4.52 − 4.60 (m, 1 H)4.22 − 4.41 (m, 3 H) 3.95 − 4.14 (m, 1 H) 3.52 − 3.67 (m, 1 H) 2.32 −2.40 (m, 1 H) 2.09 − 2.27 (m, 1 H) 1.87 − 2.00 (m, 2 H) 1.66 − 1.78 (m,1 H) 1.46 − 1.58 (m, 1 H) 41

10-840 (300 MHz) 8.34 − 8.67 (m, 2 H) 7.94 − 8.19 (m, 2 H) 7.48 (dd, J =8.67, 2.61 Hz, 1 H) 5.38 − 5.62 (m, 1 H) 5.18 − 5.38 (m, 1 H) 4.50 −4.85 (m, 1 H) 4.17 − 4.49 (m, 2 H) 3.97 − 4.14 (m, 1 H) 1.60 − 2.43 (m,12 H) 42

451.2 (300 MHz) 8.53 (s, 1 H) 8.41 (d, J = 10.55 Hz, 1 H) 8.07 (d, J =2.93 Hz, 1 H) 7.98 (s, 1 H) 7.86 (dd, J = 8.89, 2.66 Hz, 1 H) 5.37 (brs, 1 H) 5.23 − 5.32 (m, 1 H) 4.69 − 4.84 (m, 1 H) 4.49 − 4.61 (m, 2 H)4.31 (br d, J = 15.31 Hz, 1 H) 2.23 − 2.39 (m, 2 H) 2.01 − 2.19 (m, 4 H)1.67 − 1.96 (m, 5 H) 1.50 − 1.64 (m, 1 H) 43

441.2 (300 MHz) 8.50 − 8.67 (m, 1 H) 7.36 − 8.20 (m, 4 H) 5.21 − 5.52(m, 2 H) 4.85 − 5.11 (m, 1 H) 3.70 − 4.67 (m, 6 H) 2.97 − 3.19 (m, 1 H)2.03 − 2.42 (m, 2 H) 1.87 − 2.02 (m, 2 H) 1.66 − 1.83 (m, 1 H) 1.56 (brd, J = 10.73 Hz, 1H) 44

425.1 (300 MHz) 9.40 (dd, J = 7.61, 2.11 Hz, 1 H) 8.55 (s, 1 H) 8.07 (d,J = 2.93 Hz, 1 H) 7.94 − 8.02 (m, 2 H) 5.11 − 5.27 (m, 2 H) 4.60 (ddd, J= 10.41, 7.34, 3.16 Hz, 1 H) 4.51 (t, J = 3.76 Hz, 1 H) 4.33 (d, J =14.95 Hz, 1 H) 3.86 − 4.01 (m, 1 H) 3.15 (ddd, J = 13.25, 8.76, 2.57 Hz,1 H) 2.28 − 2.42 (m, 1 H) 2.03 − 2.22 (m, 1 H) 1.85 − 2.00 (m, 2 H) 1.66− 1.82 (m, 1 H) 1.49 − 1.64 (m, 1 H) 1.45 (d, J = 6.24 Hz, 3 H) 45

465.2 (300 MHz) 8.43 − 8.62 (m, 1 H) 7.86 − 8.13 (m, 4 H) 5.35 − 5.56(m, 1 H) 4.65 − 4.93 (m, 1 H) 4.49 − 4.62 (m, 1 H) 4.40 − 4.48 (m, 1 H)4.25 (br d, J = 14.40 Hz, 1 H) 4.06 − 4.17 (m, 1 H) 3.15 − 3.27 (m, 2 H)2.09 − 2.35 (m, 4 H) 1.84 − 2.00 (m, 4 H) 1.67 − 1.77 (m, 3 H) 1.46 −1.58 (m, 1 H) 46

437.1 (300 MHz) 8.97 − 9.10 (m, 1 H) 8.53 − 8.68 (m, 1 H) 7.96 − 8.11(m, 3 H) 5.44 − 5.59 (m, 1 H) 5.12 (q, J = 4.49 Hz, 1 H) 4.50 − 4.71 (m,3 H) 4.24 − 4.42 (m, 1 H) 2.79 − 3.10 (m, 2 H) 2.30 − 2.42 (m, 1 H) 2.03− 2.22 (m, 2 H) 1.87 − 2.01 (m, 2 H) 1.49 − 1.82 (m, 3 H) 47

461.1 (300 MHz) 9.83 (d, J = 9.08 Hz, 1 H) 8.59 (s, 1 H) 8.11 (d, J =2.84 Hz, 1 H) 8.00 − 8.08 (m, 2 H) 6.10 − 6.56 (m, 1 H) 5.32 (dd, J =14.76, 1.38 Hz, 1 H) 4.87 (br dd, J = 11.60, 4.81 Hz, 1 H) 4.52 − 4.67(m, 2 H) 4.30 − 4.48 (m, 3 H) 2.35 − 2.45 (m, 1 H) 2.08 − 2.20 (m, 1 H)1.89 − 1.99 (m, 2 H) 1.69 − 1.81 (m, 1 H) 1.49− 1.63 (m, 1 H) 48

479.1 (300 MHz) 10.07 (d, J = 8.71 Hz, 1 H) 8.60 (s, 1 H) 8.13 (d, J =2.93 Hz, 1 H) 8.04 − 8.11 (m, 2 H) 5.18 − 5.28 (m, 1 H) 4.95 − 5.08 (m,2 H) 4.63 (ddd, J = 10.34, 7.36, 3.12 Hz, 1 H) 4.36 − 4.51 (m, 3 H) 2.39(br d, J = 10.64 Hz, 1 H) 2.11 − 2.20 (m, 1 H) 1.91 − 2.00 (m, 2 H) 1.75(br d, J = 8.07 Hz, 1 H) 1.55 − 1.64 (m, 1 H) 49

441.1 (300 MHz) 9.12 (t, J = 5.00 Hz, 1 H) 8.62 (s, 1 H) 8.06 (d, J =2.93 Hz, 1 H) 8.00 (s, 1 H) 7.55 (dd, J = 8.67, 2.80 Hz, 1 H) 5.35 (dd,J = 14.81, 1.51 Hz, 1 H) 5.18 (t, J = 5.73 Hz, 1 H) 5.08 (t, J = 5.87Hz, 1 H) 4.26 − 4.38 (m, 2 H) 4.10 − 4.17 (m, 1 H) 3.76 − 3.91 (m, 2 H)3.63 − 3.72 (m, 1 H) 3.41 (ddd, J = 13.25, 6.14, 4.17 Hz, 1 H) 2.56 −2.65 (m, 1 H) 2.14 − 2.28 (m, 1 H) 1.91 − 2.01 (m, 2 H) 1.63 − 1.86 (m,2 H)

Biologic Assays

In-Vitro Assays

Materials and Methods

Biochemical Kinase Assay Method

The biochemical kinase assay was performed at Reaction BiologyCorporation (www.reactionbiology.com, Malvern, Pa.) following theprocedures described in the reference (Anastassiadis T, et al NatBiotechnol. 2011, 29, 1039). Specific kinase/substrate pairs along withrequired cofactors were prepared in reaction buffer; 20 mM Hepes pH 7.5,10 mM MgCl₂, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na₃VO₄, 2mM DTT, 1% DMSO. Compounds were delivered into the reaction, followed˜20 minutes later by addition of a mixture of ATP (Sigma, St. Louis Mo.)and ³³P ATP (Perkin Elmer, Waltham Mass.) to a final concentration of 10μM. Reactions were carried out at room temperature for 120 min, followedby spotting of the reactions onto P81 ion exchange filter paper (WhatmanInc., Piscataway, N.J.). Unbound phosphate was removed by extensivewashing of filters in 0.75% phosphoric acid. After subtraction ofbackground derived from control reactions containing inactive enzyme,kinase activity data was expressed as the percent remaining kinaseactivity in test samples compared to vehicle (dimethyl sulfoxide)reactions. IC₅₀ values and curve fits were obtained using Prism(GraphPad Software).

Cell Lines and Cell Culture:

Human medulla thyroid carcinoma cell line TT (containing RET M918Tmutation) and acute myelogenous cell line KG-1 were purchased from ATCC.Human colon cancer cell line KM12 (containing TPM3-TRKA) was obtainedfrom NCI.

Cloning and Ba/F3 stable cell line creation

The EML4-ALK gene (variant 1) was synthesized at GenScript and clonedinto pCDH-CMV-MCS-EF1-Puro plasmid (System Biosciences, Inc).Ba/F3-EML4-ALK wild type were generated by transducing Ba/F3 cells withlentivirus containing EML4-ALK wide type. Stable cell lines wereselected by puromycin treatment, followed by IL-3 withdrawal. Briefly,5×10⁶ Ba/F3 cells were transduced with lentivirus supernatant in thepresence of 8 μg/mL protamine sulfate. The transduced cells weresubsequently selected with 1 μg/mL puromycin in the presence ofIL3-containing medium RPMI1640, plus 10% FBS. After 10-12 days ofselection, the surviving cells were further selected for IL3 independentgrowth.

The KIF5B-RET gene was synthesized at GenScript and cloned intopCDH-CMV-MCS-EF1-Puro plasmid (System Biosciences, Inc). KIF5B-RET pointmutation V804M was generated at GenScript by PCR and confirmed bysequencing. Ba/F3-KIF5B-RET wild type and mutant were generated bytransducing Ba/F3 cells with lentivirus containing KIF5B-RET wide typeor mutant. Stable cell lines were selected by puromycin treatment,followed by IL-3 withdrawal. Briefly, 5×10⁶ Ba/F3 cells were transducedwith lentivirus supernatant in the presence of 8 μg/mL protaminesulfate. The transduced cells were subsequently selected with 1 μg/mLpuromycin in the presence of IL3-containing medium RPM11640, plus 10%FBS. After 10-12 days of selection, the surviving cells were furtherselected for IL3 independent growth.

Cell Proliferation Assays:

Two thousand cells per well were seeded in 384 well white plate for 24hrs, and then treated with compounds for 72 hours (37° C., 5% CO₂). Cellproliferation was measured using CellTiter-Glo luciferase-based ATPdetection assay (Promega) following the manufactures's protocol. IC₅₀determinations were performed using GraphPad Prism software (GraphPad,Inc., San Diego, Calif.).

Immunoblotting for Cellular Kinase Phosphorylation Assays

Half a million cells per well were seeded in 24 well plate for 24 hrs,and then treated with compounds for 4 hours. Cells were collected aftertreatment and lysed in RIPA buffer (50 mM Tris, pH 7.4, 150 mM NaCl, 1%NP-40, 0.5% Deoxycholate, 0.1% SDS) supplemented with 10 mM EDTA, 1×Halt protease and phosphatase inhibitors (Thermo Scientific). Proteinlysates (approximately 20 μg) was resolved on 4-12% Bolt Bis-Trisprecasted gels with MES running buffer (Life Technologies), transferredto nitrocellulose membranes using Trans-Blot Turbo Transfer System(Bio-Rad) and detected with antibodies targeting phosphorylated RET(Y905) (Cell Signaling Technology), total RET (Cell SignalingTechnology), actin (Cell Signaling Technology). Antibodies weretypically incubated overnight at 4° C. with gentle shake, followed bywashes and incubation with the appropriate HRP-conjugated secondaryantibodies. Membranes were incubated with chemiluminescent substrate for5 min at room temperature (SuperSignal West Femto, Thermo Scientific).The chemiluminescent images were acquired with a C-DiGit Imaging System(LI-COR Biosciences). The relative density of the chemiluminescent bandswere quantified via Image Studio Digits from LICOR. The half inhibitoryconcentration (ICso) value is calculated using non-linear regressionanalysis through GraphPad Prism software (GraphPad, Inc., San Diego,Calif.).

Data and Results:

Enzymatic kinase activities of Compound 1 and 5.

IC₅₀ (nM) at IC₅₀ (nM) at 10 μM ATP 10 μM ATP Enzyme Compound 1 Compound5 RET 0.0994 1.01 RET (A883F) 0.520 3.08 RET (E762Q) 2.07 0.58 RET(G691S) 3.01 0.941 RET (L790F) 0.120 1.31 RET (M918T) 0.114 1.42 RET(R749T) 0.271 0.32 RET (R813Q) 0.341 2.46 RET (S891A) 0.664 0.303 RET(S904A) 0.159 1.22 RET (S904F) 0.0621 0.364 RET (V778I) <0.0508 0.233RET (V804L) 10.0 2350 RET (V804M) 7.86 18.8 RET (Y791F) <0.0508 7.95 RET(Y806H) 0.385 0.261 RET-CCDC6 (PTC1) 0.0893 1.97 RET-NC0A4 (PTC3) 0.06350.691 RET-PRKAR1A (PTC2) 0.129 0.29 Src 0.875 1.46 FYN 1.81 1.94 YES1.72 2.64 HCK 1.95 2.71 LYN 1.97 2.03

Anti-Cell Proliferation Activity

TT cell BaF3 BaF3 KIF5B- BaF3 KIF5B- KM12 cell BaF3 KG-1 (RET C634W)KIF5B-RET RET_V804M RET_G810R (TPM3-TRKA) Cpd EML4-ALK IC₅₀ (nM) IC₅₀(nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) 1 211.4 131.2 <0.5 0.251002 30 3.0 2 >10000 5000 1784 1452 >10000 254.9 3 1500 505 7.9 <0.21704 4.2 4 3287 5000 461.9 184.4 5000 22 5 515.6 26.8 0.9 2.4 598 22 6.96 145.5 1 0.2 573.1 3 0.2 7 674.8 343.8 0.2 1845 99.2 37 8 4000 188.9341.8 1928 0.3 9 8000 1000 2364 >10000 3.3 10 4000 78.3 274.4 1213 0.211 10000 307.3 838.9 3000 0.4 12 2709 159.9 100.5 4619 1014 13.8 13 5000452 341.5 >10000 1121 28.4 14 907.8 273 120.3 10000 530 26.6 15 364.45.2 1.1 1245 8.7 5.1 16 340.5 47.4 16.6 5000 41.2 45.5 17 615.6 5 1.82731 10.7 4 18 77.2 16.9 7.1 1533 24.4 11.3 19 895.1 73.1 5.2 3073 787.8 20 1400 2.4 1.1 1855 7.8 0.5 21 461.7 86.9 — <0.2 3459 82 13.8 22157.5 155.8 — <0.2 1763 127.6 49.3 23 1682 228.2 — 98.9 3000 422.2 52.924 468.9 8.7 — 1.8 1222 73.6 2.8 25 3000 677.3 — 193.3 3000 559.1 277.326 1412 737.1 160 5000 323.2 210.1 27 1000 0.3 — <0.2 2000 63 0.3 28803.5 22.8 — 1.5 2000 72 11.8 29 901 7.9 — 0.3 1377 133.7 1.7 30 2000853.2 — 161.9 337.2 1857 13.5 31 10000 10000 — 4000 >10000 >10000 365 321056 223 — 89 5718 500.8 20.2 33 2000 356.2 — 197.9 4000 1196 124.5 341000 407.5 — 62.2 10000 651.1 50 35 1105 55.7 — 8.8 — — <0.2 36 >1000010000 — 8000 — — 1000 37 >10000 3000 — 8000 — — 1201 38 82.1 <0.2 — <0.2349.3 0.3 <0.2 39 151.5 59.2 — 10.2 3000 57.3 7.4 40 1951 19.1 — <0.25000 1.8 <0.2 41 1448 389.2 — 5.1 — 155.6 431.2 42 338.5 41 — 0.5 — 17.49.8 43 2991 359.4 — 68.9 — 395.9 108.6 44 >10000 >10000— >10000 >10000 >10000 668.5 45 3109 1134 — 525.7 5000 1712 202.4 4655.5 5.9 — <0.2 71.5 2.9 2.8 47 139.2 3.5 — <0.2 469.3 3.6 <0.2 48 455.9117 — 0.2 1067 90.9 5.9 49 >10000 5238 — 396.6 5000 1643 1457

Compound 5 Inhibited the Phosphorylation of RET

The pharmacodynamic inhibiting activity of Compound 5 on RET inRET-driven cells was evaluated, and the results were shown in FIGS. 1, 2and 3. Compound 5 caused the suppression of RET autophosphorylation atIC50s of around 0.3, 1-3 and 3-10 nM in TT, Ba/F3 KIF5B-RET WT and Ba/F3KIF5B-RET G810R respectively (FIGS. 1,2 & 3).

In Vivo Methods

Cell Lines

BaF3 KIF5B-RET WT and BaF3 KIF5B-RET G810R cells were cultured usingstandard techniques in RPMI-1640 medium (Corning, Inc) with 10% fetalbovine serum (Thermo Fisher Scientific, Inc) at 37° C. in a humidifiedatmosphere with 5% CO₂. TT cells were cultured using standard techniquesin F-12K medium (Corning, Inc) with 10% fetal bovine serum (ThermoFisher Scientific, Inc) at 37° C. in a humidified atmosphere with 5%CO₂. For implantation, cells were harvested and pelleted bycentrifugation at 250 g for 2 minutes. Cells were washed once andresuspended in serum-free medium supplemented with 50% matrigel (v/v).

Subcutaneous Xenograft Models in Immune Compromised Mice

For cell derived xenograft models, female SCID/Beige mice (5-8 weeks ofage) were obtained from Charles River Laboratory and were housed inInnovive IVC disposable cages on HEPA filtered ventilated racks with adlibitum access to rodent chow and water. Five million cells in 100 μLserum-free medium supplemented with 50% matrigel (Corning, Inc) wereimplanted subcutaneously in the right flank region of the mouse. Tumorsize and body weight were measured on designated days. Tumor size wasmeasured with an electronic caliper and tumor volume was calculated asthe product of length*width²*0.5. Mice were randomized by tumor sizeinto treatment groups when tumor volume reached about 200 mm³ andCompound 5 was administered orally (BID) at determined doses.

For PDX models, primary human tumor xenograft model LU2503 tumors weregrown in stock mice. Tumor fragments (2-3 mm in diameter) were harvestedfrom stock mice an dinoculated into the right front back of each femaleBALB/c nude mice for tumor development. Tumor size and body weight weremeasured on designated days. Tumor size was measured with an electroniccaliper and tumor volume was calculated as the product oflength*width2*0.5. Mice were randomized by tumor size into treatmentgroups when tumor volume reached about 200 mm3 and Compound 5 wasadministered orally (BID) at determined doses.

Antitumor Efficacy of Compound 5 in Xenograft Tumor Models

The antitumor efficacy of Compound 5 was evaluated in several tumorxenograft models representing cancer populations in which dysregulationof RET is implicated.

TT Thyroid Medullary Carcinoma Model

The C634W mutation of RET in TT cells underlies the molecular mechanismfor tumor growth. SCID/Beige mice bearing TT tumors (at the averagetumor size of around 200 mm³) were dosed with Compound 5 orally BID for27 days (FIG. 4A). The control group of mice were given vehicle only.Tumor volume (TMV) was measured by caliper on the indicated days and isshown at mean±sem in FIG. 4A. The mean TMVs are significantly lower inthe treated groups compared to that of the control group (p<0.0001) asdetermined by two-way repeated ANOVA followed by post hoc analysis.Tumor growth inhibition (TGI) was calculated as100%*{1−[(TMV_(Treated Last Day of Treatment)−TMV_(Treated First Day of Treatment))/(TMV_(Control on Last Day of Treatment)−TMV_(Control on First Day of Treatment))]}whenTMV_(Treated Last Day of Treatment)>TMV_(Treated First Day of Treatment).In the case ofTMV_(Treated Last Day of Treatment)<TMV_(Treated First Day of Treatment),tumor regression (REG) was calculated as100%*(1−TMV_(Treated Last Day of Treatment)/TMV_(Treated First Day of Treatment)).In this study, Compound 5 demonstrated the ability to induce tumorregression of 27% and 35% at the dose of 2 mg/kg BID and 5 mg/kg BID,respectively. Tumor size was reduced in 10 out 10 mice treated withCompound 5 at both dose levels. Body weight of the mice were measured onthe designated days of the mice as shown in FIG. 4B. No body weight lossor overt abnormality was observed at either dose levels.

Inhibition of the growth of BaF3 KIF5B-RET WT tumors and BaF3 KIF5B-RETG810R tumors following oral administration of Compound 5

In the BaF3 KIF5B-RET WT and BaF3 KIF5B-RET G810R xenograft tumormodels, the growth of tumor is presumably dependent on the extopic RETactivity. SCID/Beige mice bearing BaF3 KIF5B-RET WT tumors (with averagetumor size of ˜210 mm³) were dosed with Compound 5 orally BID for 10days (FIG. 5A). The control group of mice were given vehicle only. Tumorvolume (TMV) was measured by caliper on the indicated days and is shownat mean±sem in FIG. 5A. The mean TMVs are lower in the groups treatedwith compound 5 at 1 mg/kg BID (p>0.05) and 5 mg/kg BID (p<0.0001)compared to that of the control group as determined by two-way repeatedANOVA followed by post hoc analysis. Compound 5 demonstrated the abilityto inhibit tumor growth at 21% at the dose of 1 mg/kg BID. Compound 5treatment at 5 mg/kg BID resulted in a tumor regression of 63%, withtumor size reduction in 9 out 10 mice. Body weight of the mice weremeasured on the designated days of the mice as shown in FIG. 5B. No bodyweight loss or overt abnormality was observed in compound 5 treatmentgroups. SCID/Beige mice bearing BaF3 KIF5B-RET G810R tumors (withaverage tumor size of ˜170 mm³) were dosed with Compound 5 orally BIDfor 14 days (FIG. 6A). The control group of mice were given vehicleonly. Tumor volume (TMV) was measured by caliper on the indicated daysand is shown at mean±sem in FIG. 6A. The mean TMVs are lower in thegroups treated with compound 5 at 1 mg/kg BID (p>0.05), 5 mg/kg BID(p<0.0001) and 10 mg/kg BID (p<0.0001) compared to that of the controlgroup as determined by two-way ANOVA followed by post hoc analysis.Compound 5 treatment at 1 mg/mg BID inhibited tumor growth with a TGI of22%. Compound 5 treatment at 5 mg/kg BID resulted in a tumor regressionof 39%, with tumor size reduction in 9 out 10 mice. Compound 5 treatmentat 10 mg/kg BID resulted in complete tumor regression in 9 out 9 mice.Body weight of the mice were measured on the designated days of the miceas shown in FIG. 6B. No body weight loss or overt abnormality wasobserved in compound 5 treatment groups during the treatment period.

CR1520 Patient Derived Xenograft (PDX) Colorectal Cancer Model

The CR1520 is a PDX model derived from a colorectal cancer patientharboring the NCOA4-RET fusion gene. Treating mice bearing CR1520 tumorswith Compound 5 at 1 mg/kg BID for 21 days resulted inhibited tumorgrowth with a TGI of 63%, with tumors grew from 187 mm³ to 872 mm³. Forcomparison, the tumors grew from 187 mm³ to 2044 mm³ in the vehicletreated group (FIG. 7A). Treating mice bearing CR1520 tumors withCompound 5 at 5 mg/kg BID for 21 days resulted a tumor regression from187 mm³ to 138 mm³, corresponding to a 26% tumor regression (FIG. 7A).No body weight loss was observed after 21 days of BID treatment withCompound 5 at 1 mg/kg BID or 5 mg/kg BID (FIG. 7B).

CTG-0838 Patient Derived Xenograft (PDX) NSCLC Model

The CTG-0838 is a PDX model derived from a non-small cell lung cancerpatient harboring the KIF5B-RET fusion gene. Treating mice bearingCTG-0838 tumors with Compound 5 at 1 mg/kg BID and 2 mg/kg BID for 10days resulted inhibited tumor growth with a TGI of 71% and 76%,respectively (FIG. 8A). Treating mice bearing CTG-0838 tumors withCompound 5 at 5 mg/kg BID for 10 days resulted a tumor regression from197 mm³ to 174 mm³, corresponding to a 12% tumor regression (FIG. 8A).No body weight loss was observed after 10 days of BID treatment withCompound 5 at the 1, 2 or 5 mg/kg BID (FIG. 8B).

1. A compound of the formula I

wherein each L is independently —C(R¹)(R²)— or X; with the proviso that,when t is 1, then L is —C(R¹)(R²)—; X is O, S, S(O) or S(O)₂; each R¹and R² is independently H, deuterium, halogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, —OR^(a),—OC(O)R^(a), —OC(O)R^(a), —OC(O)NR^(a)R^(b), —OS(O)R^(a), —OS(O)₂R^(a),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b),—OS(O)NR^(a)R^(b), —OS(O)₂NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)OR^(b), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)S(O)R^(b),—NR^(a)S(O)₂R^(b), —NR^(a)S(O)NR^(a)R^(b), —NR^(a)S(O)₂NR^(a)R^(b),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b), —PR^(a)R^(b),—P(O)R^(a)R^(b), —P(O)₂R^(a)R^(b), —P(O)NR^(a)R^(b), —P(O)₂NR^(a)R^(b),—P(O)OR^(a), —P(O)₂OR^(a), —CN, or —NO₂, or R¹ and R² taken togetherwith the carbon or carbons to which they are attached form a C₃-C₆cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogenatom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3-to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, mono- or bicyclicheteroaryl, 4- to 6-membered heterocycloalkyl is independentlyoptionally substituted by deuterium, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, —OR^(e),—OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e),—S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(c)C(O)R, —NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(e)R^(f),—NR^(e)S(O)R^(f), —NR^(e)S(O)₂R^(f), —NR^(e)S(O)NR^(e)R^(f),—NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(f),—PR^(e)R^(f), —P(O)R^(e)R^(f), —P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f),—P(O)₂NR^(e)R^(f), —P(O)OR^(e), —P(O)₂OR^(e), —CN, or —NO₂; M is CR3 orN; M¹ is CR4; each R³, R⁴, and R⁵ is independently hydrogen, deuterium,halogen, —OR^(c), —OC(O)R^(c), —OC(O)NR^(c)R^(d), —OC(═N)NR^(c)R^(d),—OS(O)R^(c), —OS(O)₂R^(c), —OS(O)NR^(c)R^(d), —OS(O)₂NR^(c)R^(d),—SR^(c), —S(O)R^(c), —S(O)₂R^(c), —S(O)NR^(c)R^(d), —S(O)₂NR^(c)R^(d),—NR^(c)R^(d), —NR^(c)C(O)R^(d), —NR^(c′)C(O)OR^(d),—NR^(c)C(O)NR^(c)R^(d), —NR^(c)C(═N)NR^(c)R^(d), —NR^(c)S(O)R^(d),—NR^(c)S(O)₂R^(d), —NR^(c)S(O)NR^(c)R^(d), —NR^(c)S(O)₂NR^(c)R^(d),—C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(d), —C(═N)NR^(c)R^(d),—PR^(c)R^(d), —P(O)R^(c)R^(d), —P(O)₂R^(c)R^(d), —P(O)NR^(c)R^(d),—P(O)₂NR^(c)R^(d), —P(O)OR^(c), —P(O)₂OR^(c), —CN, —NO₂, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, or R⁴and R⁵ taken together with the ring to which they are attached form aC₅-C₈ cycloalkyl, or a 5- to 8-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, mono- orbicyclic heteroaryl, C₅-C₈ cycloalkyl, or 5- to 8-memberedheterocycloalkyl is independently optionally substituted by deuterium,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OR^(e), —OC(O)R^(e),—OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f), —NR^(e)R^(f), —NR^(e)C(O)R^(f),—NR^(e)(O)OR^(f), —NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f),—NR^(e)S(O)₂R^(f), —NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f),—C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f),—P(O)R^(e)R^(f), —P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f),—P(O)OR^(e), —P(O)₂OR^(e), —CN, or —NO₂; R⁶ is H, deuterium, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- orbicyclic heteroaryl is independently optionally substituted bydeuterium, halogen, C₃-C₆ cycloalkyl, or 5- to 7-memberedheterocycloalkyl, —OR^(e), —OC(O)R^(e), —OC(O)NR^(e)R^(f),—OC(═N)NR^(e)R^(f), —OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(e)R^(f),—OS(O)₂NR^(e)R^(f), —SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f),—S(O)₂NR^(e)R^(f), —NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)(O)OR^(f),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f), —NR^(e)S(O)₂R^(f),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e),—P(O)₂OR^(e), —CN, or —NO₂; R⁷ and R⁸ combine to form a C₃-C₇cycloalkyl, a 5- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to7-membered heteroaryl; wherein each hydrogen atom in C₃-C₇ cycloalkyl, a5- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-memberedheteroaryl is independently optionally substituted by deuterium,halogen, —OR^(e), —OC(O)R^(e), —OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f),—OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f),—NR^(e)R^(f), —NR^(e)C(O)R^(f), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f), —NR^(e)S(O)₂R^(f),—NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f), —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f), —P(O)R^(e)R^(f),—P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f), —P(O)OR^(e),—P(O)₂OR^(e), —CN, or —NO₂; Y is O, S, NR⁹, or CR9R¹⁰; R⁹ and R¹⁰ areeach independently H, deuterium, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl,C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atomin C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is optionally substituted by a halogen, —OR^(e), —OC(O)R^(e),—OC(O)NR^(e)R^(f), —OC(═N)NR^(e)R^(f), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(e)R^(f), —OS(O)₂NR^(e)R^(f), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f), —NR^(e)R^(f), —NR^(e)C(O)R^(f),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(e)R^(f), —NR^(e)S(O)R^(f),—NR^(e)S(O)₂R^(f), —NR^(e)S(O)NR^(e)R^(f), —NR^(e)S(O)₂NR^(e)R^(f),—C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(f), —PR^(e)R^(f),—P(O)R^(e)R^(f), —P(O)₂R^(e)R^(f), —P(O)NR^(e)R^(f), —P(O)₂NR^(e)R^(f),—P(O)OR^(e), or —P(O)₂OR^(e); each R^(a), R^(b), R^(c), R^(d), R^(e),and R^(f) is independently selected from the group consisting of H,deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 7-memberedheteroaryl; each of Z¹, Z², Z³, Z⁴, Z⁵, and Z⁶ is independently N, NH, Cor CH; p is 1, 2, 3, or 4; and t is 1, 2, 3, 4, or 5; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein p is
 1. 3. Thecompound of claim 2, or a pharmaceutically acceptable salt thereof,wherein t is 3 or
 4. 4. The compound of claim 1, having the formula III

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim4, or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3.6. The compound of claim 1, having the formula IV or V

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim5, or a pharmaceutically acceptable salt thereof, wherein Y is O.
 8. Thecompound of claim 7, or a pharmaceutically acceptable salt thereof,wherein M is CR³.
 9. The compound of claim 8, or a pharmaceuticallyacceptable salt thereof, wherein R³ is H, deuterium, C₁-C₆ alkyl orhalogen.
 10. The compound of claim 7, or a pharmaceutically acceptablesalt thereof, wherein M is N. 11.-28. (canceled)
 29. A method oftreating cancer comprising administering to a subject in need of suchtreatment an effective amount of at least one compound of claim 1, or apharmaceutically acceptable salt thereof.
 30. A method of inhibiting RETor SRC, comprising contacting a cell comprising one or more of suchkinases with an effective amount of at least one compound of claim 1, ora pharmaceutically acceptable salt thereof, and/or with at least onepharmaceutical composition of the disclosure, wherein the contacting isin vitro, ex vivo, or in vivo.